Angiotensin ii antagonists incorporating a substituted indole or dihydroindole

ABSTRACT

Substituted heterocycles attached through a methylene bridge to novel substituted indole or dihydroindole derivative of the Formula I are useful as angiotensin II antagonists. ##STR1##

BACKGROUND OF THE INVENTION

The Renin-angiotensin system (RAS) plays a central role in theregulation of normal blood pressure and seems to be critically involvedin hypertension development and maintenance as well as congestive heartfailure. Angiotensin II (A II), is an octapeptide hormone producedmainly in the blood during the cleavage of angiotensin I by angiotensinconverting enzyme (ACE) localized on the endothelium of blood vessels oflung, kidney, and many other organs. It is the end product of therenin-angiotensin system (RAS) and is a powerful arterialvasoconstrictor that exerts its action by interacting with specificreceptors present on cell membranes. One of the possible modes ofcontrolling the RAS is angiotensin II receptor antagonism. Severalpeptide analogs of A II are known to inhibit the effect of this hormoneby competitively blocking the receptors, but their experimental andclinical applications have been limited by partial agonist activity andlack of oral absorption [M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46(1982); D. H. P. Streeten and G. H. Anderson, Jr.--Handbook ofHypertension, Clinical Pharmacology of Antihypertensive Drugs. ed. A. E.Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, TheNetherlands, 1984].

Recently, several non-peptide compounds have been described as A IIantagonists. Illustrative of such compounds are those disclosed in U.S.Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804 andin European Patent Applications 028,834; 245,637; 253,310: and 291,969;and in articles by A. T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 157,13-21 (1988)] and by P. C. Wong, et al. [J. Pharm. Exp. Therap. 247,1-7(1988)]. All of the U.S. Patents, European Patent Applications028,834 and 253,310 and the two articles disclose substituted imidazolecompounds which are generally bonded through a lower alkyl bridge to asubstituted phenyl. European Patent Application 245,637 disclosesderivatives of 4,5,6,7-tetrahydro-2H-imidazo[4,5-c]pyridine-6-carboxylic acid and analogs thereof as antihypertensiveagents.

None of the compounds disclosed in any US Patent, European Applicationsor literature publication are of the type containing substitutedheterocycles bonded through an alkyl bridge to a novel substitutedphenyl of the type disclosed herein. The quinazolin-4(1H)-ones,triazolinones, triazolinimines, and pyrimidinones have been disclosed inearlier U.S. Patent applications focusing on the heterocyclic fragmentof the antagonist design. The serial numbers of these applications areU.S. Ser. Nos. 351,508; 358,971; 375,655; 360,673; 375,217; and 386,328.A related application discloses 6-membered ring fused imidazolesincorporating an indole or dihydroindole moiety.

BRIEF DESCRIPTION OF THE INVENTION

This invention is directed to substituted heterocycles attached througha methylene bridge to novel substituted indole or dihydroindolederivatives to give compounds of the Formula I, which are angiotensin IIantagonists and are useful in the treatment of hypertension andcongestive heart failure. The compounds of the invention are useful asocular antihypertensives.

Specifically, the compounds of this invention contain a heterocyclicmoiety which is substituted at the specified positions and to which amethylene bridge connecting a novel substituted indole or dihydroindolegroup as defined by the lower portion of Formula I, is attached.Additionally, pharmaceutically acceptable compositions of these novelcompounds, as the sole therapeutically active ingredient and incombination with diuretics and other antihypertensive agents, includingbeta blockers, angiotensin converting enzyme inhibitors, calcium channelblockers or a combination thereof are disclosed and claimed. Further,methods of treating hypertension and congestive heart failure aredescribed and claimed.

The compounds of this invention have central nervous system (CNS)activity. They are useful in the treatment of cognitive dysfunctionsincluding Alzheimer's disease, amnesia and senile dementia. Thesecompounds also have anxiolytic and antidepressant properties and aretherefore, useful in the relief of symptoms of anxiety and tension andin the treatment of patients with depressed or dysphoric mental states.

In addition, these compounds exhibit antidopaminergic properties and arethus useful to treat disorders that involve dopamine dysfunction such asschizophrenia. The compounds of this invention are especially useful inthe treatment of these conditions in patients who are also hypertensiveor have a congestive heart failure condition.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of the general Formula I: ##STR2##and the heterocycle is specifically defined as: ##STR3## R¹ is: (a) (C₁-C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which isunsubstituted or substituted with a substituent selected from the groupconsisting of:

i) aryl as defined below,

ii) (C₃ -C₇)-cycloalkyl,

iii) Cl, Br, I, F,

iv) OH,

v) NH₂,

vi) NH(C₁ -C₄)-alkyl,

vii) N[(C₁ -C₄) alkyl]₂,

viii) NHSO₂ R²,

ix) CF₃,

x) COOR², or

xi) SO₂ NHR^(2a),

(b) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstitutedor substituted with 1 or 2 substituents selected from the groupconsisting of:

i) Br, I, Cl, F,

ii) (C₁ -C₄)-alkyl,

iii) (C₁ -C₄)-alkoxy,

iv) NO₂

v) CF₃

vi) SO₂ NR^(2a) R^(2a),

vii) (C₁ -C₄)-alkylthio,

viii) hydroxy,

ix) amino,

x) (C₃ -C₇)-cycloalkyl, or

xi) (C₃ -C₁₀)-alkenyl;

(c) heteroaryl, wherein heteroaryl is defined as a 5 or 6- memberedheteroaromatic moiety, which can contain one or two members selectedfrom the group consisting of N, O, S and wherein the heteroaryl isunsubstituted, monosubstituted or disubstituted with substituentsselected from the group consisting of:

i) Cl, Br, I, or F,

ii) OH,

iii) SH,

iv) NO₂,

v) (C₁ -C₄)-alkyl,

vi) (C₂ -C₄)-alkenyl,

vii) (C₂ -C₄)-alkynyl,

viii) (C₁ -C₄)-alkoxy, or

ix) CF₃, or

(d) (C₁ -C₄)-perfluoroalkyl;

E is:

(a) a single bond,

(b) --S(O)_(n) (CH₂)_(s) --, or

(c) --O--;

n is 0 to 2;

s is 0 to 5;

J¹ is (a)--C(═M)--, (b) J¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b) or c) J¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom not at J¹, substituted withR^(7a), R^(7b), R^(8a) and R^(8b) ;

K¹ is (a)--C(═M)--, (b) K¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b), or c) K¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom , substituted on the carbonatoms with R^(7a), R^(7b) and R^(8b) ;

one of a¹ or b¹ is a double bond in structures Ia provided that when J¹is --C(═M)-- then b¹ is a double bond and when K¹ is --C(═M)-- then a¹is a double bond;

L is the point of attachment the 6-membered fused aromatic ringoptionally containing one nitrogen atom;

J² is (a)--C(═M)--, or (b)--C(R¹⁷)--;

K² is (a)--C(═M)--, or (b)--C(R¹⁷)--, provided that one and only one ofJ² and K² is --C(═M)--,

one of a² or b² is a double bond in structure Ic provided that when J²is --C(═M)-- then b² is a double bond and when K² is --C(═M)-- then a²is a double bond.

M is O, S or NR¹⁵ ;

R² is:

(a) H, or

(b) (C₁ -C₆)-alkyl;

R^(2a) is:

(a) R²,

(b) CH₂ -aryl, or

c) aryl;

R^(7a) and R^(7b) are independently

(a) H,

(b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl,

c) Cl, Br, I, F,

d) CF₃, or

(e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms, they canbe joined to form a phenyl ring;

R^(8a) and R^(8b) are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl,

(c) heteroaryl-(C₁ -C₄)-alkyl,

(d) (C₁ -C₆)-alkyl, which is unsubstituted or substituted with asubstituent selected from the group consisting of: --CON(R^(2a))₂,--heteroaryl, --S(O)_(x) --R²¹, --tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂NH-heteroaryl, --SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, SO₂ NH--CN,--NR² COOR²¹, --OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁-C₄)-alkylthio, (C₁ -C₄)-alkyl-amino, (C₁ -C₄)-dialkylamino,--COOR^(2a), --CONHR^(2a), --O--COR^(2a), or aryl,

(e) --CO-aryl,

(f) (C₃ -C₇)-cycloalkyl,

(g) Cl, Br, I, F,

(h) --OH,

(i) --OR²¹,

(j) --SH,

(k) --S(O)_(n) --(C₁ -C₄)-alkyl,

(l) --COR^(2a),

(m) --CO₂ H,

(n) --CO₂ --(C₁ -C₄)-alkyl,

(o) --SO₃ H,

(p) --NR² R²¹,

(q) --NR² COR²¹,

(r) --NR² COOR²¹,

(s) --SO₂ NHR^(2a),

(t) --SO₂ NR² R^(2a),

(u) --NO₂,

(v) --NHSO₂ CF₃,

(w) --CONR^(2a) R^(2a),

(x) --(C₁ -C₄)-perfluoroalkyl,

(y) --COOR²,

(z) --SO₃ H,

(aa) --N(R²)SO₂ R²¹,

(bb) --NR² CONR⁴ R²¹,

(cc) --OC(═O)NR²¹ R^(2a),

(dd) --aryl,

(ee) --NHSO₂ CF₃,

(ff) --SO₂ NH-heteroaryl,

(gg) --SO₂ NHCOR²¹,

(hh) --CONHSO₂ R²¹,

(ii) --PO(OR²)₂,

(jj) --tetrazol-5-yl,

(kk) --CONH(tetrazol-5-yl),

(ll) --SO₂ NHCN, or

(mm) --heteroaryl;

X is:

(a) O,

(b) H, H,

(c) H; CO₂ --(C₁ -C₄)-alkyl,

(d) H, CO₂ H,

(e) H; CN,

(f) H; tetrazolyl, or

(g) H; CONHSO₂ R¹⁴,

R⁹ and R¹⁰ are each independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) (C₁ -C₆)-alkyl

(e) (C₁ -C₆)-acyloxy,

(f) (C₃ -C₆)-cycloalkyl,

(g) (C₁ -C₆)-alkoxy,

(h) --NHSO₂ R^(2a),

(i) hydroxy-(C₁ -C₄)-alkyl,

(j) (C₁ -C₄)-alkyl-aryl,

(k) S(O)_(n) --(C₁ -C₄)-alkyl,

(n) NR^(2a) R^(2a),

(q) CF₃,

(r) --SO₂ NHR^(2a),

(s) furyl,

(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, NO₂, CF₃,(C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--CO₂ H, or --CO₂ --(C₁ -C₄)-alkyl, or

(u) when R⁹ and R¹⁰ are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring:

R¹¹ and R¹² are independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) NH₂,

(e) NH[(C₁ -C₄)-alkyl],

(f) N[(C₁ -C₄)-alkyl]₂,

(g) SO₂ NHR^(2a),

(h) CF₃,

(i) (C₁ -C₄)-alkyl,

(j) (C₁ -C₄)-alkoxy, or

(k) when R¹¹ and R¹² are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

Z is:

(a) --H,

(b) --CO₂ R^(2a),

(c) --SO₃ R¹³,

(d) --NHSO₂ CF₃,

(e) --PO(OR¹³)₂,

(f) --SO₂ NHR¹⁴,

(g) CONHOR¹³, ##STR4## (i) --CN, (j) --SO₂ NH-heteroaryl, whereinheteroaryl is an unsubstituted, monosubstituted or disubstituted five orsix membered aromatic ring which can contain from 1 to 3 heteroatomsselected from the group consisting of O, N or S and wherein thesubstituents are members selected from the group consisting of: --OH,--SH, --(C₁ -C₄)-alkyl, --(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂,--CO₂ H, --CO₂ --(C₁ -C₄)-alkyl, --NH₂, NH[(C₁ -C₄)-alkyl] and --N[(C₁-C₄)-alkyl]₂,

(k) --CH₂ SO₂ NH-heteroaryl.

(l) --SO₂ NH--CO--R¹⁴,

(m) --CH₂ SO₂ NH--CO--R¹⁴,

(n) --CONH--SO₂ R¹⁴,

(o) --CH₂ CONH--SO₂ R¹⁴,

(p) --NHSO₂ NHCO--R¹⁴,

(q) --NHCONHSO₂ --R¹⁴,

(r) --NHCO₂ R^(2a), ##STR5## R¹⁴ is (a) aryl,

(b) heteroaryl,

(c) (C₃ -C₇)-cycloalkyl, or

(d) (C₁ -C₄)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: aryl, heteroaryl, --OH, --SH, (C₁-C₄)-alkyl, --(C₁ -C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I,--NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃H or PO(OH)(O--(C₁ -C₄)-alkyl);

R¹⁵ is

(a) H,

(b) aryl, which is unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl,(C₁ -C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl,--OH, --NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl;

(c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of: aryl, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F,--OH, --NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or

(d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered ring which can contain one or two heteroatoms selected from thegroup consisting of N, O, S, and wherein the substituents are membersselected from the group consisting of --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy, --CF₃, Cl, Br, I, F, or NO₂ ;

R¹⁶ is

(a) (C₁ -C₁₀)-alkyl,

(b) substituted (C₁ -C₁₀)-alkyl in which one or two substituent(s)selected from the group consisting of:

(1) I, Br, Cl, F,

(2) hydroxy,

(3) (C₁ -C₁₀)-alkoxy,

(4) (C₁ -C₅)-alkoxycarbonyl,

(5) (C₁ -C₅)-acyloxy,

(6) (C₃ -C₈)-cycloalkyl,

(7) aryl,

(8) substituted aryl, in which the substituents are V and W,

(9) (C₁ -C₁₀)-alkyl-S(O)_(n),

(10) (C₃ -C₈)-cycloalkyl-S(O)_(n),

(11) phenyl-S(O)_(n),

(12) substituted phenyl-S(O)_(n), in which the substituents are V and W,

(13) oxo,

(14) carboxy,

(15) NR^(2a) R^(2a), or

(16) (C₁ -C₅)alkylaminocarbonyl,

(c) perfluoro-(C₁ -C₄)-alkyl,

(d) (C₂ -C₁₀)-alkenyl,

(e) (C₂ -C₁₀)-alkynyl,

(f) (C₃ -C₈)-cycloalkyl,

(g) substituted (C₃ -C₈)-cycloalkyl, in which the substituent isselected from:

(1) (C₁ -C₅)-alkyl, or

(2) (C₁ -C₅)-alkoxy;

(h) aryl,

(i) substituted aryl, in which the substituents are V and W,

(j) aryl-(CH₂)_(r) --(M₁)_(z) --(CH₂)_(t) --,

(k) substituted aryl-(CH₂)_(r) --(M₁)_(z) (CH₂)_(t) -- in which the arylgroup is substituted with V and W, ##STR6## (q) --[(C₁ -C₄)-alkyl]NR²R²¹, (r) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(s) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(t) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(u) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(v) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(w) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

V and W are each independently selected from:

(a) H,

(b) (C₁ -C₅)-alkoxy,

(c) (C₁ -C₅)-alkyl,

(d) hydroxy,

(e) (C₁ -C₅)-alkyl-S(O)_(n),

(f) --CN,

(g) --NO₂,

(h) --NR² R^(2a),

(i) (C₁ -C₅)-acyl-NR² R^(2a),

(j) --CO₂ R^(2a),

(k) (C₁ -C₅)-alkyl-carbonyl,

(l) CF₃,

(m) I, Br, Cl, F,

(n) hydroxy-(C₁ -C₄)-alkyl--,

(o) carboxy-(C₁ -C₄)-alkyl--,

(p) --tetrazol-5-yl,

(q) --NH--SO₂ CF₃, or

(r) aryl;

M₁ is M or --C(O)--;

z is 0 or 1;

r and t are 0 to 2;

R¹⁷ and R¹⁸ are each independently selected from:

(a) H,

(b) aryl-(C₁ -C₄)-alkyl--,

(c) heteroaryl-(C₁ -C₄)-alkyl ,

(d) (C₁ -C₄)-alkyl unsubstituted or substituted with a substituentselected from the group consisting of --OH, --NH₂, guanidino, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), --O--COR^(2a), CF₃ ;

(e) (C₁ -C₄)-alkenyl,

(f) --CO-aryl,

(g) (C₃ -C₇)-cycloalkyl,

(h) Cl, Br, I, F,

(i) --OH,

(j) --O--(C₁ -C₄)-alkyl,

(k) --(C₁ -C₄)-perfluoroalkyl,

(l) --SH,

(m) --S(O)_(n) --(C₁ -C₄)-alkyl,

(n) --CHO,

(o) --CO₂ R^(2a),

(p) --SO₃ H,

(q) --NH₂,

(r) --NH[(C₁ -C₄)-alkyl],

(s) --N[(C₁ -C₄)-alkyl]₂,

(t) --NHCO₂ --(C₁ -C₄)-alkyl,

(u) --SO₂ NR² R^(2a),

(v) --CH₂ OCOR^(2a),

(w) --NH--SO₂ --(C₁ -C₄)-alkyl,

(x) 5 or 6 membered saturated heterocycle containing one nitrogen atomand optionally containing one other heteroatom selected from N, O, or S,such as pyrrolidine, morpholine, or piperazine,

(y) aryl,

(z) heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ringcontaining one or two heteroatoms selected from the group consisting ofO, N, or S,

(aa) tetrazol-5-yl,

(bb) --[(C₁ -C₄)-alkyl]NR² R²¹,

(cc) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(dd) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(ee) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(ff) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(gg) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(hh) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

R¹⁹ is:

(a) H,

(b) (C₁ -C₆)-alkyl,

(c) (C₂ -C₄)-alkenyl,

(d) (C₁ -C₄)-alkoxy, or

(e) benzyl, wherein the phenyl is unsubstituted or substituted with asubstituent selected from the group consisting of: --NO₂, --NH₂, --OH or--OCH₃ ;

R²⁰ is --CN, --NO₂, CO₂ R^(2a), or CF₃ ; and

R²¹ is:

(a) aryl, or

(b) (C₁ -C₄)-alkyl, is unsubstituted or substituted with:

i) NH₂,

ii) NH[(C₁ -C₄)-alkyl],

iii) N[(C₁ -C₄)-alkyl]₂,

iv) CO₂ H,

v) CO₂ (C₁ -C₄)-alkyl,

vi) OH,

vii) SO₃ H, or

viii) SO₂ NH₂ ;

or a pharmaceutically acceptable salt thereof.

Wherein a preferred embodiment is when:

R¹ is:

(a) (C₁ -C₆)-alkyl or (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with a substituent selected from thegroup consisting of:

i) (C₁ -C₄)-alkylthio,

ii) (C₁ -C₄)-alkoxy,

iii) CF₃,

iv) CF₂ CF₃, or

v) (C₃ -C₅)-cycloalkyl,

(b) perfluoro-(C₁ -C₄)-alkyl, or

(c) (C₃ -C₅)-cycloalkyl,

E is:

(a) single bond,

(b) --S--, or

(c) --O--,

J¹ is (a) --C(═M)--, (b) J¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b) or (c) J¹ and L are connected together to form a 6-memberedaromatic ring containing one nitrogen atom not at J¹, substituted withR^(7a), R^(7b), R^(8a) and R^(8b) ;

K¹ is (a) --C(═M)--, or (b) K¹ and L are connected together to form a6-carbon aromatic ring substituted with R^(7a), R^(7b), R^(8a) andR^(8b), or (c) K¹ and L are connected together to form a six-memberedaromatic ring containing one nitrogen atom substituted with R^(7a),R^(7b) and R^(8a) provided that one and only one of J¹ and K¹ is--C(═M)--,

one of a¹ or b¹ is a double bond in structure Ia provided that when J¹is --C(═M)-- then b¹ is a double bond and when K¹ is --C(═M)-- then a¹is a double bond;

L is the point of attachment of the 6-membered fused aromatic ringoptionally containing one nitrogen atom;

J² is (a) --C(═M)--, or (b) --C(R¹⁷)--;

K² is (a) --C(═M)--, or (b) --C(R¹⁷)--, provided that one and only oneof J² and K² is --C(═M)--;

one of a² or b² is a double bond in structure Ic provided that when J²is --C(═M)--then b² is a double bond and when K² is --C(═M)--then a² isa double bond.

M is O, S or NR¹⁵ ;

R² is:

(a) H,

(b) (C₁ -C₆)-alkyl;

R^(2a) is:

(a) R²,

(b) CH₂ aryl, or

(c) aryl;

R^(7a) and R^(7b) are independently

(a) H,

(b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl,

(c) Cl, Br, I, F,

(d) CF₃, or

(e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms, they canbe joined to form a phenyl ring;

R^(8a) and R^(8b) are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl,

(c) heteroaryl-(C₁ -C-4)-alkyl,

(d) (C₁ -C₆)-alkyl, is unsubstituted or substituted with a substituentselected from the group consisting of: --CON(R^(2a))₂, --heteroaryl,--S(O)_(x) R²¹, --tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂ NH-heteroaryl,--SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN, --NR² COOR²¹,--OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁-C₄)-alkylamino, (C₁ -C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a),--O--COR^(2a), or aryl,

(e) --CO-aryl,

(f) (C₃ -C₇)-cycloalkyl,

(g) Cl, Br, I, F,

(h) --OH,

(i) --OR²¹,

(j) --SH,

(k) --S(O)_(n) --(C₁ -C₄)-alkyl,

(l) --COR^(2a),

(m) --CO₂ H,

(n) --CO₂ --(C₁ -C₄)-alkyl,

(o) --SO₃ H,

(p) --NR² R²¹,

(q) --NR² COR²¹,

(r) --NR² COOR²¹,

(s) --SO₂ NR²¹,

(t) --SO₂ NR² R^(2a),

(u) --NO₂,

(v) --NHSO₂ CF₃,

(w) --CONR^(2a) R^(2a),

(x) --(C₁ -C₄)-perfluoroalkyl,

(y) --COOR²,

(z) --SO₃ H,

(aa) --N(R²)SO₂ R²¹,

(bb) --NR² CONR^(2a) R²¹,

(cc) --OC(═O)NR²¹ R^(2a),

(dd) --aryl,

(ee) --NHSO₂ CF₃,

(ff) --SO₂ NH-heteroaryl,

(gg) --SO₂ NHCOR²¹,

(hh) CONHSO₂ R²¹,

(ii) --PO(OR²)₂,

(jj) --tetrazol-5-yl,

(kk) --CONH(tetrazol-5-yl),

(ll) --SO₂ NHCN, or

(mm) --heteroaryl;

X is:

(a) O,

(b) H; H,

(c) H; CO₂ --(C₁ -C₄)-alkyl,

(d) H; CO₂ H,

(e) H; CN,

(f) H; tetrazolyl, or

(g) H; CONHSO₂ R¹⁴,

R⁹ and R¹⁰ are each independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) (C₁ -C₆)-alkyl,

(e) (C₁ -C₆)-acyloxy,

(f) (C₃ -C₆)-cycloalkyl,

(g) (C₁ -C₆)-alkoxy,

(h) --NHSO₂ R^(2a),

(i) hydroxy-(C₁ -C₄)-alkyl,

(j) (C₁ -C₄)-alkyl-aryl,

(k) S(O)_(n) --(C₁ -C₄)-alkyl,

(n) NR^(2a) R^(2a),

(q) CF₃,

(r) --SO₂ NHR^(2a),

(s) furyl,

(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, NO₂, CF₃,(C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--CO₂ H, or --CO₂ --(C₁ -C₄)-alkyl, or

(u) when R⁹ and R¹⁰ are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

R¹¹ and R¹² are independently:

(a) H,

(b) Cl, Br, I, F,

(c) NO₂,

(d) NH₂,

(e) NH[(C₁ -C₄)-alkyl],

(f) N[(C₁ -C₄)-alkyl]₂,

(g) SO₂ NHR^(2a),

(h) CF₃,

(i) (C₁ -C₄)-alkyl,

(j) (C₁ -C₄)-alkoxy, or

(k) when R¹¹ and R¹² are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring;

Z is:

(a) H,

(b) --CO₂ R^(2a),

(c) --NHSO₂ CF₃,

(d) --SO₂ NHR^(2a),

(e) --CN,

(f) --SO₂ NH-heteroaryl, wherein heteroaryl is an unsubstituted,monosubstituted or disubstituted five or six membered aromatic ringwhich can optionally contain from 1 to 3 heteroatoms selected from thegroup consisting of O, N or S and wherein the substituents are membersselected from the group consisting of --OH, --SH, --(C₁ -C₄)-alkyl,--(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, --CO₂ --C₁ -C₄-alkyl, --NH₂, NH[(C₁ -C₄)-alkyl] and --N[(C₁ -C₄ -alkyl]₂,

(g) --1H-tetrazol-5-yl,

(h) --CH₂ --1H-tetrazol-5-yl,

(i) --CONH--1H-tetrazol-5-yl, or

(j) --SO₂ NHCOR¹⁴ ;

R¹⁵ is:

(a) H,

(b) aryl, is unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of Cl, Br, I, F, --O--(C₁ -C₄)-alkyl,(C₁ -C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl,--OH, --NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl;

(c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of: aryl, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F,--OH, --NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or

(d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered ring which contains one or two heteroatoms selected from thegroup consisting of N, O, S, and wherein the substituents are membersselected from the group consisting of --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ;

R¹⁶ is:

(a) (C₁ -C₁₀)-alkyl,

(b) substituted (C₁ -C₁₀)-alkyl in which one or two substituent(s) is(are) selected from:

(1) hydroxy,

(2) (C₁ -C₅)-alkoxy,

(3) (C₁ -C₅)-alkoxycarbonyl,

(4) phenyl,

(5) carboxy, or

(6) C(═O)NH--(C₁ -C₅)-alkyl;

(c) aryl, or

(d) aryl substituted with V and W;

V and W are selected from:

(a) H,

(b) (C₁ -C₅)-alkoxy,

(c) (C₁ -C₅)-alkyl,

(d) hydroxy,

(e) --CN,

(f) NO₂,

(g) --NR² R^(2a),

(h) --CO₂ R^(2a),

(i) --CF₃,

(j) I, Br, Cl, F,

(k) hydroxy-(C₁ -C₄)-alkyl--,

(l) tetrazol-5-yl,

(m) --NH--SO₂ CF₃,

(n) --[(C₁ -C₄)-alkyl]NR² R²¹,

(o) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(p) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(q) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(r) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(s) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(t) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

R¹⁷ and R¹⁸ are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl--,

(c) heteroaryl-(C₁ -C₄)-alkyl--,

(d) (C₁ -C₄)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: --OH, --NH₂, guanidino, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), or --O--COR^(2a), CF₃,

(e) (C₁ -C₄)-alkenyl,

(f) --CO-aryl,

(g) (C₃ -C₇)-cycloalkyl,

(h) Cl, Br, I, F,

(i) --OH,

(j) --O--(C₁ -C₄)-alkyl,

(k) --(C₁ -C₄)-perfluoroalkyl,

(l) --SH,

(m) --S(O)_(n) --(C₁ -C₄)-alkyl,

(n) --CHO,

(o) --CO₂ R^(2a),

(p) --SO₃ H,

(q) --NH₂,

(r) --NH[(C₁ -C₄)-alkyl],

(s) --N[(C₁ -C₄)-alkyl]₂,

(t) --NHCO₂ --(C₁ -C₄)-alkyl,

(u) --SO₂ NR² R^(2a),

(v) --CH₂ OCOR^(2a),

(w) --NH--SO₂ --(C₁ -C₄)-alkyl,

(x) 5 or 6 membered saturated heterocycle containing one nitrogen atomand optionally containing one other heteroatom selected from N, O, or S,such as pyrrolidine, morpholine, or piperazine,

(y) aryl,

(z) heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ringcontaining one or two heteroatoms selected from the group consisting ofO, N, or S;

(aa) tetrazol-5-yl, or

(bb) --[(C₁ -C₄)-alkyl]NR² R²¹,

(cc) --[(C₁ -C₄)-alkyl]NR² COR²¹,

(dd) --[(C₁ -C₄)-alkyl]NR² COOR²¹,

(ee) --[(C₁ -C₄)-alkyl]CONR^(2a) R^(2a),

(ff) --[(C₁ -C₄)-alkyl]N(R²)SO₂ R²¹,

(gg) --[(C₁ -C₄)-alkyl]NR² CONR⁴ R²¹, or

(hh) --[(C₁ -C₄)-alkyl]OC(═O)NR²¹ R^(2a) ;

R²¹ is

(a) aryl, or

(b) (C₁ -C₄)-alkyl which is unsubstituted or substituted with:

i) NH₂,

ii) NH[(C₁ -C₄)-alkyl],

iii) N[(C₁ -C₄)-alkyl]₂,

iv) CO₂ H,

v) CO₂ (C₁ -C₄)-alkyl,

vi) OH,

vii) SO₃ H, or

viii) SO₂ NH₂ ;

or a pharmaceutically acceptable salt thereof

Wherein a more preferred embodiment of the invention is when:

R¹ is:

(a) (C₁ -C₆)-alkyl (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which isunsubstituted or substituted with a substituent selected from the groupconsisting of:

i) (C₁ -C₄)-alkylthio,

ii) (C₁ -C₄)-alkoxy,

iii) CF₃,

iv) CF₂ CF₃, or

v) (C₃ -C₅)-cycloalkyl, or

(b) (C₁ -C₄)-perfluoroalkyl,

E is a single bond;

J¹ and L are connected together to form a 6-carbon aromatic ringsubstituted with R^(7a), R^(7b), R^(8a) and R^(8b) ; or J¹ and L areconnected together to form a 6-membered aromatic ring containing onenitrogen atom not at J¹, substituted with R^(7a), R^(7b), R^(8a) andR^(8b) ;

K¹ is --C(═M)--;

a¹ is a double bond;

L is the point of attachment of the 6-membered fused aromatic ringoptionally containing one nitrogen atom;

J² is --C(R¹⁷)--;

K² is --C(═M)--;

a² is a double bond;

M is O, or NR¹⁵ ;

R² is:

(a) H,

(b) (C₁ -C₆)-alkyl, or

(c) (C₁ -C₆)-alkyl;

R^(2a) is:

(a) R²,

(b) benzyl, or

(c) phenyl;

R^(7a) and R^(7b) are independently:

(a) H,

(b) (C₁ -C₆)-alkyl, C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl,

(c) Cl, Br, I, F,

(d) CF₃, or

(e) when R^(7a) and R^(7b) are bonded to adjacent carbon atoms, they canbe joined to form a phenyl ring;

R^(8a) and R^(8b) are independently:

(a) H,

(b) aryl-(C₁ -C₄)-alkyl,

(c) heteroaryl-(C₁ -C₄)-alkyl,

(d) (C₁ -C₆ -alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: --CON(R^(2a))₂, --heteroaryl,--S(O)_(n) --R²¹, --tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂ NH-heteroaryl,--SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN, --NR² COOR²¹,--OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁-C₄)-alkylamino, (C₁ -C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a),--O--COR^(2a), or aryl,

(e) --CO-aryl,

(f) (C₃ -C₇)-cycloalkyl,

(g) Cl, Br, I, F,

(h) --OH,

(i) --OR²¹,

(j) --SH,

(k) --S(O)_(n) --(C₁ -C₄)-alkyl,

(l) --COR^(2a),

(m) --CO₂ H,

(n) --CO₂ --(C₁ -C₄)-alkyl,

(o) --SO₃ H,

(p) --NR² R²¹,

(q) --NR² COR²¹,

(r) --NR² COOR²¹,

(s) --SO₂ NR^(2a),

(t) --SO₂ NR² R^(2a),

(u) --NO₂,

(v) --NHSO₂ CF₃,

(w) --CONR^(2a) R^(2a),

(x) --(C₁ -C₄)-perfluoroalkyl,

(y) --COOR²,

(z) --SO₃ H,

(aa) --N(R²)SO₂ R²¹,

(bb) --NR² CONR⁴ R²¹,

(cc) --OC(═O)NR²¹ R^(2a),

(dd) --aryl,

(ee) --NHSO₂ CF₃,

(ff) --SO₂ NH-heteroaryl,

(gg) --SO₂ NHCOR²¹,

(hh) --CONHSO₂ R²¹,

(ii) --PO(OR²)₂,

(jj) --tetrazol-5-yl,

(kk) --CONH(tetrazol-5-yl),

(ll) --SO₂ NHCN, or

(mm) --heteroaryl,

X is:

(a) O,

(b) H; H,

(c) H; CO₂ --(C₁ -C₄)-alkyl,

(d) H; CO₂ H,

(e) H; CN,

(f) H; tetrazolyl, or

(g) H, CONHSO₂ R¹⁴,

R¹¹ and R¹² are independently:

(a) H,

(b) Cl, Br, I, F,

(c) NH₂,

(d) NH[(C₁ -C₄)-alkyl],

(e) N[(C₁ -C₄)-alkyl]₂

(f) SO₂ NHR^(2a),

(g) CF₃,

(h) C₁ -C₄ -alkyl,

(i) C₁ -C₄ -alkoxy, or

Z is:

(a) H,

(b) --CO₂ R^(2a),

(c) --NHSO₂ CF₃,

(d) --SO₂ NHR¹⁴,

(e) --1H-tetrazol-5-yl,

(f) --SO₂ NHCOR¹⁴, or

(g) NHSO₂ R¹⁴ ;

R¹⁴ is

(a) aryl,

(b) heteroaryl,

(c) (C₃ -C₇)-cycloalkyl, or

(d) (C₁ -C₄)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of aryl as defined above, heteroarylas defined above, --OH, --SH, (C₁ -C₄)-alkyl, --(C₁ -C₄ -alkoxy), --S(C₁-C₄)-alkyl, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl,--NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃ H, PO(OH)(O--(C₁ -C₄)-alkyl);

R¹⁵ is:

(a) H,

(b) aryl, unsubstituted or substituted with 1 or 2 substituents selectedfrom the group consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl, (C₁-C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl, --OH,--NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl;

(c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of whichis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of aryl as defined above, (C₃ -C₇)-cycloalkyl,Cl, Br, I, F, --OH, --NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--NH--SO₂ R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or

(d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6membered ring which can contain one or two heteroatoms selected from thegroup consisting of N, O, S, and wherein the substituents are membersselected from the group consisting of: --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ;

R¹⁶ is

(a) (C₁ -C₁₀)-alkyl,

(b) substituted (C₁ -C₁₀)-alkyl in which one or more substituent(s) isselected from

(1) hydroxy,

(2) (C₁ -C₅)-alkoxy,

(3) (C₁ -C₅)-alkoxycarbonyl,

(4) phenyl,

(5) carboxy, or

(6) C(═O)NH--(C₁ -C₅)-alkyl,

(c) aryl, or

(d) aryl substituted with V and W;

V and W are selected from:

(a) H,

(b) (C₁ -C₅)-alkoxy,

(c) (C₁ -C₅)-alkyl,

(d) hydroxy,

(e) --CN,

(f) --NO₂,

(g) --NR² R^(2a),

(h) --CO₂ R^(2a),

(i) --CF₃,

(j) I, Br, Cl, F,

(k) hydroxy-(C₁ -C₄)-alkyl ,

(l) --1H-tetrazol-5-yl, or

(m) --NH--SO₂ CF₃ ;

R¹⁷ and R¹⁸ are independently

(a) H,

(b) aryl-(C₁ -C₄)-alkyl--,

(c) heteroaryl-(C₁ -C₄)-alkyl--,

(d) (C₁ -C₄)-alkyl, unsubstituted or substituted with a substituentselected from the group consisting of: --OH, --NH₂, guanidino, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), --O--COR^(2a), CF₃ ;

(e) (C₁ -C₄)-alkenyl,

(f) --CO-aryl,

(g) (C₃ -C₇)-cycloalkyl,

(h) Cl, Br, I, F,

(i) --OH,

(j) --O--(C₁ -C₄)-alkyl,

(k) --(C₁ -C₄)-perfluoroalkyl,

(l) --SH,

(m) --S(O)_(n) --(C₁ -C₄)-alkyl,

(n) --CHO,

(o) --CO₂ R^(2a),

(p) --SO₃ H,

(q) --NH₂,

(r) --NH](C₁ -C₄)-alkyl],

(s) --N[(C₁ -C₄)-alkyl]₂,

(t) --NHCO₂ --(C₁ -C₄)-alkyl,

(u) --SO₂ NR² R^(2a),

(v) --CH₂ OCOR^(2a),

(w) --NH--SO₂ --(C₁ -C₄)-alkyl,

(x) 5 or 6 membered saturated heterocycle containing one nitrogen atomand optionally containing one other heteroatom selected from N, O, or S,such as pyrrolidine, morpholine, or piperazine,

(y) aryl,

(z) heteroaryl, or

(aa) tetrazol-5-yl; and

R²¹ is:

(a) aryl, or

(b) (C₁ -C₄)-alkyl which is unsubstituted or substituted with:

i) NH₂,

ii) NH[(C₁ -C₄)-alkyl],

iii) N[(C₁ -C₄)-alkyl]₂,

iv) CO₂ H,

v) CO₂ (C₁ -C₄)-alkyl,

vi) OH,

vii) SO₃ H, or

viii) SO₂ NH₂ ;

or a pharmaceutically acceptable salts thereof.

The alkyl substitutents recited above denote straight and branched chainhydrocarbons of the length specified such as methyl, ethyl, isopropyl,isobutyl, neopentyl, isopentyl, etc.

The alkenyl and alkynyl substituents denote alkyl groups as describedabove which are modified so that each contains a carbon to carbon doublebond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.

Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each whichmay be substituted or unsubstituted with other hydrocarbon substituents,and include for example cyclopropyl, cyclopentyl, cyclohexyl and4-methylcyclohexyl.

The alkoxy substituent represents an alkyl group as described aboveattached through an oxygen bridge.

The aryl substituent recited above represents phenyl or naphthyl.

The heteroaryl substituent recited above represents any 5- or 6-memberedaromatic ring containing from one to three heteroatoms selected from thegroup consisting of nitrogen, oxygen, and sulfur, for example, pyridyl,thienyl, furyl, imidazolyl, and thiazolyl.

GENERAL METHODS FOR PREPARATION OF COMPOUNDS OF GENERAL FORMULA I

The methods described in PART I AND PART II below illustrate thepreparation of angiotensin II antagonists of Formula I. There areseveral general approaches to the synthesis of antagonists of Formula I,and it is taken as a general principle that one or another method may bemore readily applicable for the preparation of a given antagonist; someof the approaches illustrated below may not be readily applicable forthe preparation of certain antagonists of Formula I.

It should be recognized that antagonists of Formula I consist of aheterocyclic component designated above by formulas Ia through Ic and abenzyl or benzoyl substituted indole or dihydroindole substituent whichis attached to the heterocyclic component at a nitrogen atom. Thus, twogenerally applicable approaches to antagonists of formula I are these:

1. A heterocycle, designated above with Formulas Ia through Ic isprepared as described in PART I below. Then the heterocycle is alkylatedat a nitrogen atom with N-benzoyl-5-(halomethyl)indole or itspseudohalide giving the compounds of Formula I. The preparation ofN-benzoyl-5-(halomethyl)indole is described in Part II below. Thisalkylating agent is often designated as "Ar--CH₂ Q where Q is a halide(--Cl,Br,I) or pseudohalide (--OMs, OTs, OTf). In some cases, alkylationmay take place at more than one nitrogen atom of the heterocycle, and inthese cases, separation by fractional crystallization or bychromotographic methods may be necessary for isolation of the desiredproduct. In some cases, the alkylation step produces a fully assembledantagonist of Formula I, except that functional groups in the alkylatingagent or in the heterocycle may be present in protected form and requiredeprotection steps to be carried out to complete the synthesis. In mostcases, the alkylation is carried out with only a partially assembledindole and requires the alkylation with a substituted benzyl/benzoylelement be carried out in subsequent steps to give the antagonist ofFormula I. The alkylation steps and subsequent steps used to prepareantagonists of Formula I, are described in PART II below.

The compounds of this invention may be resolved using techniques knownin the art. The enantiomers are separated and the desired compound isthe more active stereoisomer. The compounds of this invention, theirpharmaceutically acceptables and their prodrug forms are included withinthe scope of this invention.

Abbreviations used in the schemes and examples are listed in Table 1.

                  TABLE 1                                                         ______________________________________                                        Reagents                                                                      NBS             N-bromosuccinimide                                            AIBN            Azo(bis)isobutyronitrile                                      DDQ             Dichlorodicyanoquinone                                        Ac.sub.2 O      acetic anhydride                                              TEA             triethylamine                                                 DMAP            4-dimethylaminopyridine                                       PPh.sub.3       triphenylphosphine                                            TFA             trifluroacetic acid                                           TMS-Cl          trimethylsilyl chloride                                       Im              imidazole                                                     AcSK            potassium thioacetate                                         p-TsOH          p-toluenesulfonic acid                                        FMOC-Cl         9-Fluorenylmethyloxycarbonyl                                                  chloride                                                      Solvents:                                                                     DMF             dimethylformamide                                             HOAc (AcOH)     acetic acid                                                   EtOAc (EtAc)    ethyl acetate                                                 Hex             hexane                                                        THF             tetrahydrofuran                                               DMSO            dimethylsulfoxide                                             MeOH            methanol                                                      iPrOH           isopropanol                                                   Others:                                                                       rt              room temperature                                              TBDMS           t-butyldimethylsilyl                                          OTf             OSO.sub.2 CF.sub.3                                            Ph              phenyl                                                        FAB-MS (FSBMS)  Fast atom bombardment mass                                    spectroscopy                                                                  NOE             Nuclear Overhauser Effect                                     SiO.sub.2       silica gel                                                    trityl          triphenylmethyl                                               Bn              benzyl                                                        ______________________________________                                         ##STR7##

Scheme I-1 illustrates the preparation of 1,2-disubstitutedquinazolin-4(1H)-ones of Formula Ia wherein J¹ =--C(O)-- and E is asingle bond. An appropriately substituted anthranilonitrile is acylatedusing the requisite acyl chloride. The resulting amide is alkylated withsodium hydride and the appropriate alkyl halide (or pseudohalide). Theresulting tertiary amide is then rearranged/cyclized with basic hydrogenperoxide¹. ##STR8##

2-Substituted quinazolinones may be prepared from substitutedanthranilonitriles as described in the literature and illustrated inScheme I-2. The appropriately substituted anthranilonitrile is acylatedusing the requisite acyl chloride then cyclized using basic hydrogenperoxide.¹ ##STR9##

Scheme I-3 shows an alternate preparation of 2-substitutedquinazolinones starting with the corresponding anthranilic acid. Theappropriately substituted anthranilic acid is treated with twoequivalents of the requisite acyl chloride in DMF with triethylamine andDMAP at 0° C. This is then heated to 110° C. for two hours after whichtime excess ammonium carbonate is added.² ##STR10##

Scheme I-4 illustrates the general preparation of 2,3-disubstitutedquinazolin-4-(3H) ones of Formula Ia, wherein E is a single bond and K¹is C(O) . An appropriately substituted 2-substituted quinazolinone (seeScheme I-2 or Scheme I-3) is alkylated using sodium hydride and theappropriate alkyl halide (or pseudohalide). This reaction sometimesgives some O-alkylated product, generally less than 20% of the isolatedreaction products. ##STR11##

Schemes I-5, I-6, and I-7 provide an alternate route to compounds ofFormula Ia, wherein E is a single bond and K¹ is --C(O)--.

Two methods for preparing 3,1,4-benzoxazones are illustrated in SchemeI-5. Substituted anthranilic acids may be acylated and cyclized byheating them in DMF with an acyl chloride, triethylamine and DMAP.³Alternatively, they may also be prepared by heating an appropriatelysubstituted anthranil with an acyl chloride in pyridine.⁴

The necessary alkyl amine may then be prepared from the alkyl halide (orpseudohalide) using the standard literature procedures (Scheme I-6).⁵Then, the amine and the 3,1,4-benzoxazone are heated together to givethe desired 2,3-disubstituted quinazolinone 2 (Scheme I-7). ##STR12##

Substituted 2-alkylthioquinazolin-4(3H)-ones wherein K¹ is --C(O)-- andE is --S-- may be prepared from their corresponding substitutedanthranilic acids as shown in Scheme I-8. The amine from Scheme I-6 canbe converted to its isothiocyanate upon treatment with thiophosgene.This may then be reacted with an appropriately substituted anthranilicacid to give the desired 3-alkyl-2-mercapto-quinazolin-4(3H)-one.⁶. Asecond alkylation of the mercapto group then gives the desired2-alkylthio-3-alkylquinazolin-4(3H) one.⁷ ##STR13##

Similarly, 2-alkoxyquinazolin-4-(3H)-ones wherein K¹ is --C(O)-- and Bis --O-- may be prepared from their corresponding substitutedanthranilic acids as shown in Scheme 9.⁸ Alkylation with the appropriatealkyl halide according to the methods developed by Lange and Sheibley ⁹then gives the final product 17. ##STR14##

Scheme I-10 illustrates a possible route to the isomeric1,2-disubstituted quinazolin-4-(1H)-ones wherein J¹ is --C(O)-- andwhere E is --S-- or --O--. An anthranilonitrile can be acylated with analkyl haloformate or an alkylthiol haloformate.¹⁰ This may then bedeprotonated and alkylated with the appropriate alkyl halide to give theintermediate carbamate nitrile shown.¹¹ Conversion of the intermediatethen could occur when the material is treated with basic hydrogenperoxide to yield the desired product 20. ##STR15##

Scheme I-11 illustrates the method by which a2-amino-3-alkylquinazolinone can be made. The 2-mercaptoquinazolinone(14) shown in Scheme I-8 can be treated with sulfuryl chloride to givethe corresponding 2-chloroquinazolinone.¹² Displacement of the chloridewith an R¹ amine then gives 20 with B=NH.¹³ ##STR16##

Scheme I-12 illustrates the method by which a2-amino-1-alkylquinazolinone can be made. The products from Scheme I-10can be used as a synthetic intermediate if the initial R¹ is aprotecting group such as benzyl or t-butyl.¹⁴ Deprotection andsubjection of the resulting 2-mercapto-1-alkyl-quinazolinone to the sameconditions used in Scheme I-11 will result in the formation of thedesired 2-amino-1-alkylquinazolin-4-(1H)-one. Alternatively, the sulfidemay be displaced directly by an R¹ amine as shown in Scheme I-13 (R¹--S-- and R¹ --NH₂ may or may not have the same R¹). ##STR17##

The preparation of quinazolinones of general Formula Ia bearingsubstituted C-6-amino groups may be accomplished as illustrated inSchemes I-14 through I-16. In order to prepare these derivatives, theamide group of a 6-nitroquinazolin-4(3H) one is usually first protectedwith an acid labile protecting group as shown in Scheme I-14. Forinstance, reaction of the generalized 6-nitroquinazolin-4-(3H) one (24)with a base such as sodium hydride in DMF followed by addition ofbis(4-methoxyphenyl)methyl chloride affords the N-protected derivative25. The nitro group of 25 may be reduced to the amine 26 by reductionwith hydrogen over palladium on carbon. The amine (26) may then bereacted with a variety of reagents known to form derivatives of aminessuch as alkyl- or aryl-carboxylic acid chlorides, chloroformates,sulfonyl and sulfamoyl chlorides, isocyanates and isothiocyanates.Scheme I-14 illustrates the derivatization of amine 26 with ageneralized chloroformate to afford substituted carbamates such as 27.The acylation of amine 26 with a chloroformate is best carried out inthe presence of a strong base such as sodium hydride to deprotonate theamine. This anion then reacts readily with chloroformates to give thesubstituted carbamates 27. The carbamate (27) may be isolated, thendeprotonated with lithium bis(trimethylsilyl)amide and alkylated to givethe N,O-disubstituted carbamates 28. Alternatively, this process may becarried out in one flask by first deprotonating the aniline (i.e. withsodium hydride in DMF), reacting the anion with an acyl halide orchloroformate, then treating the intermediate with an equivalent of astrong base such as lithium bis(trimethylsilyl)amide and finally addingan alkylating agent to obtain 28. The carbamoyl-substitutedquinazolinones 27 and 28 may be cleanly deprotected under acidicconditions such as trifluoroacetic acid-anisole to afford theheterocycles 29 and 30 respectively. ##STR18##

Scheme I-15 illustrates the reaction of amine 25 with isocyanates togive disubstituted ureas (31). Tetrasubstituted and trisubstituted ureassuch as 34 and 35 may be prepared from the benzyl carbamate 27 as shownin Scheme I-16. Thus, treatment of 27 with the magnesium salt of asecondary amine formed from the secondary amine and methylmagnesiumbromide affords the trisubstituted urea 32. Trisubstituted ureas (32)may be N-alkylated by deprotonation of the remaining hydrogen withlithium bis(trimethylsilyl)-amide followed by alkylation with an alkyliodide to give 33. The urea-substituted quinazolinones 32 and 33 may becleanly deprotected under acidic conditions such as trifluoroaceticacid-anisole to afford the heterocycles 34 and 35 respectively. Theamine 26 (Scheme I-14) may be derivatized or converted to otherfunctional groups using chemical procedures well known to those skilledin the art. After the appropriate 6-substituent has been constructed theprotecting group may be removed by treatment with trifluoroacetic acidin the presence of anisole as illustrated in Schemes I-14 through I-16.The heterocycles obtained in this manner may be incorporated intoAngiotensin II Antagonists of general Formula Ia as described in PartII. ##STR19##

For a general review of the synthesis and reactivity of2,3-disubstituted pyrido[2,3-d] or [3,4-d] or [3,2-d] or [4,3-d]pyrimidin-4-(3HO-ones, see A. R. Katritzky, et al., ComprehensiveHeterocyclic Chemistry, vol. 3, 201 (1984) and W. J. Irwin, et al.,Advances in Heterocyclic Chemistry, vol. 10, 149 (1969).

QUINAZOLINONE REFERENCES

¹ E. C. Taylor, R. J. Knopf, A. L. Borror, J. Am. Chem. Soc. (1960) 82,3152.

R. L. McKee, M. K. McKee, R. W. Bost, J. Am. Chem. Soc. (1946) 68, 1902.

A. Khan, R. K. Saksena, Pharmazie (1988) 43 H. 12.

² M. T. Bogert, W. F. Hand, J. Am. Chem. Soc. (1906) 28, 94.

³ See A. Khan, reference 1.

L. A. Errede, J. J. McBrady, H. T. Oien, J. Org. Chem. (1977) 42, 656.

L. A. Errede, J. Org. Chem. (1976) 41 1763.

L. A. Errede, H. T. Oien, D. R. Yarian, J. Org. Chem. (1977) 42, 12.

⁴ K. Wunsch, A. J. Boulton, Adv. Het. Chem. (1967) 8, pp 326-9, andreferences therein.

I. R. Gambhir, S. S. Joshi, J. Ind. Chem. Soc. (1964) 41, 47.

⁵ Bayley, Stranding, Knowles, Tetrahedron. Lett. (1978) 3633.

Rolla, J. Org. Chem. (1982) 47, 4327.

Gibson, Bradshaw, Angew. Chem. Int. Ed. Engl. (1968) 7, 919.

⁶ R. G. Dave, G. S. Mewada, G. C. Amin, J. Ind. Chem. Soc. (1960) 37,595.

⁷ J. E. McCarty, E. L. Haines, C. A. VanderWerf, J. Am. Chem. Soc.(1960) 82, 964.

P. N. Bhargava, P. Ram, Bull. Chem. Soc. Jap. (1965) 38, 342.

M. R. Chaurasia, A. K. Sharma, Heterocycles (1983) 20, 1549.

K. Lempert, G. Doleschall, Chem Ber. (1963) 96, 1271.

H. Singh, K. S. Narang, J. Ind. Chem. Soc. (1963) 40, 545.

M. S. Dhatt, K. S. Narang, J. Ind. Chem. Soc. (1954) 31, 787.

M. S. Dhatt, K. S. Narang, J. Ind. Chem. Soc. (1954) 31, 864.

D. S. Bariana, H. S. Sachdev, K. S. Narang, J. Ind. Chem. Soc. (1955)32, 647.

⁸ Griess, Ber. Deut. Chem. Ges. (1869) 2, 415.

⁹ N. A. Lang, F. E. Sheibley, J. Am. Chem. Soc. (1933) 55, 1188.

¹⁰ H. B. Milne, S. L. Razniak, R. P. Bayer, D. W. Fish, J. Am. Chem.Soc. (1960) 82, 4582.

E. J. Corey, M. G. Bock, A. P. Kozikowski, A. V. R. Rao, D. Floyd, B.Lipshutz, Tetrahedron Lett. (1978) 1051.

M. Bergmann. L. Zervas, Ber. (1932) 65 1192.

R¹¹ R. L. Dannley, M. Lukin, J. Org. Chem. (1957) 22, 268.

R. Zibuck, N. J. Liverton, A. B. Smith, J. Am. Chem. Soc. (1986) 10,82451.

¹² D. J. Brown, fused Pyrimidines, Part I Quinazolines, (1967), J. Wiley& Sons, p. 222.

¹³ D. J. Brown, Fused Pyrimidines, Part I Quinazolines, (1967), J. Wiley& Sons, p. 323.

¹⁴ T. W. Greene, Protective Groups in Organic Synthesis, (1981), J.Wiley & Sons, pp. 193-217.

B. Preparation of triazolinones, triazolinethiones and triazolinimines(Formula Ib) ##STR20##

The compounds of Formula Ib can be prepared by a variety of methodstypified by those described below in Schemes I-17to I-28. Generalsynthetic methods for 2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-onesand --triazolin-3-(4H)-thiones are discussed in books or review articlessuch as:

(1) C. Temple and J. A. Montgomery, "Triazoles: 1,2,4" (Vol. 37 of TheChemistry of Heterocyclic Compounds, A. Weissberger and E. C. Taylor,eds.), Wiley Interscience, N.Y., 1981, pp. 365-442.

(2) J. B. Polya, Comprehensive Heterocyclic Chemistry. The Structure,Reactions, Synthesis and Uses of Heterocyclic Compounds, A. R. Katritzkyand C. W. Rees, eds., Vol. 5, Pergamon Press, Oxford, 1984, pp. 733-790.

(3) J. H. Boyer, Heterocyclic Compounds, R. C. Elderfield, ed., Vol. 7,John Wiley & Sons, N.Y., 1961, pp. 384-461.

In general, the compounds of Formula Ib are constructed in such a waythat N¹ and N² of the triazole ring are derived from hydrazine or ahydrazine derivative, while N⁴ of the triazole and the 4-(arylmethyl)substituent are derived directly or indirectly from a suitablysubstituted benzylamine (or isocyanate or isothiocyanate) or from abenzyl halide (or methanesulfonate, p-toluenesulfonate, etc.).

Although the Reaction Schemes described below are reasonably general, itwill be understood by those skilled in the art of organic synthesis thatone or more functional groups present in a given compound of Formula Ibmay render the molecule incompatible with a particular syntheticsequence. In such a case an alternative route, an altered order ofsteps, or a strategy of protection and deprotection may be employed. Inall cases the particular reaction conditions (including reagents,solvent, temperature, and time) should be chosen so that they areconsistent with the nature of the functionality present in the molecule.

The Reaction Schemes below have been generalized for simplicity. It isto be understood that the "ArCH₂ " substituent present at N⁴ of thetriazole derivatives or in their precursors is any substitutedarylmethyl moiety consistent with the definition of the N⁴ substituentin Formula I or which may be transformed to such a grouping eitherbefore or after the assembly of the triazole ring system. Suchtransformations may involve protection and/or deprotection steps, asdescribed above in the "General Methods" section or other modifications.It is also to be understood that in most of the Reaction Schemes, the"ArCH₂ " (Ar=aryl) substituent is consistent with the definition ofFormula I.

It is further to be understood that in the generalized schemes below,unless specified otherwise, the R¹ and R¹⁶ groups representfunctionalized or unfunctionalized alkyl, aryl, heteroaryl, aralkyl, andthe like. The moiety, R¹⁶ Q, represents an alkylating agent in which R¹⁶is typically a functionalized or unfunctionalized alkyl or aralkylgroup, while Q is a leaving group such as chloro, bromo, iodo,methanesulfonate, or p-toluenesulfonate. In structures showing an "X"group double-bonded to a carbon atom (as in 22 and products derivedtherefrom), M is O or S. ##STR21##

One of the most widely used routes to2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-ones(2,4,5-trisubstituted-1,2,4-triazolin-3-(4H)-ones) is shown in ReactionScheme I-17 in its adaptation for the synthesis of compounds of FormulaIb. Reaction of a carboxylic acid hydrazide 1 (readily obtained from thecorresponding ester) with the appropriate arylmethyl isocyanate 2 givesthe 1-acyl-4-(arylmethyl)semicarbazide 3. The isocyanate 2 itself isobtainable by well-known methods from various sources, including the(arylmethyl)amine (by phosgene treatment), the arylmethyl halide (bytreatment with cyanate anion), and the arylacetic acid or derivative(via Curtius rearrangement of the acyl azide). Upon heating in thepresence of hydroxide or alkoxide, cyclization of 3 to the triazolinone4 occurs. Finally, in the presence of a base (e.g., sodium hydride,sodium ethoxide, sodium hydroxide, or potassium carbonate), 4 isconverted to the trisubstituted triazolinone 5 on treatment with asuitable alkylating agent R¹⁶ Q, where R¹⁶ is alkyl, aralkyl, etc., andQ is bromo, iodo, chloro, methanesulfonate, p-toluenesulfonate, and thelike. Such reaction pathways have been described by D. L. Temple, Jr.,and W. G. Lobeck, Jr., U.S. Pat. No. 4,487,773 (1984), R. E. Gammans, D.W. Smith, and J. P. Yevich, U.S. Pat. No. 4,613,600 (1986), and (inpart) H. Gehlen and W. Schade, Liebigs Ann. Chem., 675, 180 (1964), G.Palazzo, U.S. Pat. No. 3,857,845 (1974), and K. H. Hauptmann and K.Zeile, British Patent 971,606 (1964). A modified approach to anintermediate of type 3 and its subsequent cyclization to a triazolinoneanalogous to 4 have been reported by H. Hrebabecky and J. Beranek,Collect. Czech. Chem. Commun., 50, 779 (1985). ##STR22##

A highly useful alternative route to 4 is shown in Reaction Scheme I-18.This approach has been described by M. Pesson, S. Dupin, and M. Antoine,Compt. Rend., 253, 285 (1961) and R. Un and A. Ikizler, Chim. ActaTurc., 3, 113 (1975). Addition of ethyl carbazate (8) to the imidate 7(which is readily prepared from the corresponding nitrile 6) yields anadduct 9, which can be converted to the triazolinone 4 on heating withthe (arylmethyl)amine 10 (typically at temperatures from 70°-150° C.).As in Reaction Scheme I-17, 4 can be alkylated to give thetrisubstituted triazolinone 5. ##STR23##

The procedures of Reaction Schemes I-17 and I-18 are not suitable forthe introduction of most aryl or heteroaryl substituents at N². Incontrast, the procedures of Reaction Schemes I-19 to I-22 are especiallywell suited for the synthesis of compounds of Formula Ib having aryl orheteroaryl substituents at N², since the triazolinone ring isconstructed with the N² -substituent in place, whereas the N⁴-substituent is introduced subsequently by alkylation. Reaction SchemeI-19 presents a route patterned after that reported by K. Yabutani, K.Taninaka, M. Kajioka, K. Takagi, H. Matsui, K. Sutoh, and M. Yamamoto,European Patent Application 220, 952 (1987). The N-carbethoxy imidate 11(obtained by reaction of 7 with ethyl chloroformate) is treated with anarylhydrazine 12 (or analog), typically at about 40°-50° C.) in thepresence of a tertiary amine such as triethylamine which effectscyclization to the triazolinone 13. In the presence of a suitable base(e.g., sodium hydride, sodium alkoxide, sodium hydroxide) treatment of13 with the appropriate ArCH₂ Q, where Q=bromo, iodo, chloro,methane-sulfonate, p-toluenesulfonate, and the like, yields the N⁴-alkylated product 15. A variant of the method using a thioimidate hasbeen described by M. Kajioka, H. Kurono, K. Okawa, and M. Harada, U.S.Pat. No. 4,318,731 (1982). ##STR24##

An alternative route to the N² -substituted triazolinone intermediate 13is shown in Reaction Scheme I-20. This chemistry has been described byT. N. Ghosh and M. V. Betrabet, J. Indian Chem. Soc., 7, 899 (1930), S.Bellioni, Ann. Chim. (Rome), 52, 187(1962), G. Palazzo and G. Picconi,Boll. Chim. Farm., 105, 217 (1966), and British Patent 1,021,070 (1966).An acid chloride 16 is heated with urethane (17) (typically at 80°-100°C.), to give the acylurethane 18. Reaction of 18 with an arylhydrazine12 and phosphorus pentoxide (usually in toluene or xylene at reflux)gives 13, which can then be further alkylated on N⁴ as in ReactionScheme I-19. A (thioacyl)urethane modification of this pathway has beenreported by D. L. Temple, Jr., and W. G. Lobeck, Jr., U.S. Pat. No.4,487,773 (1984). ##STR25##

A variation of Reaction Scheme I-20, shown in Reaction Scheme I-21, hasbeen described by P. Gold-Aubert, D. Melkonian, and L. Toribio, Helv.Chim. Acta. 47, 1188 (1964) and A. L. Langis, U.S. Pat. No. 3,499,000(1970). The readily prepared acylurea 19 upon heating with anarylhydrazine 12 (at about 150°-200° C.) is converted to thetriazolinone intermediate 13. ##STR26##

In a quite different approach (Reaction Scheme I-22), L. Maravetz, U.S.Pat. No. 4,705,557 (1987) and G. Theodoridis, International PatentApplication WO87/03782 (1987) disclose condensing an α-keto acid 20 withthe arylhydrazine 12 to give derivatives such as 21, which can beconverted to the triazolinone intermediate 13 by heating withdiphenylphosphoryl azide and triethylamine (typically at 75°-115° C.).In the last step, an intermediate acyl azide loses nitrogen andundergoes the Curtius rearrangement to an isocyanate, which undergoesring closure. As shown in Reaction Scheme I-19, 13 can then be alkylatedon N⁴ to give the trisubstituted triazolinone 15. ##STR27##

2,4,5-Trisubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones(2,4,5-trisubstituted-1,2,4-triazolin-3-(4H)-thiones) cannot generallybe prepared by routes analogous to those in Reaction Schemes I-17 toI-22 because of the propensity for alkylation to occur on sulfur ratherthan on the open ring nitrogen. It is thus preferable to have all of thesubstituents in place at the time of the ring closure to form theheterocycle. As shown in Reaction Scheme I-23, for certain R¹⁶ groups(e.g., R¹⁶ =CH₃), reaction of the hydrazine derivative 23 with theappropriate isocyanate or isothiocyanate 22 yields the 2,4-disubstitutedsemicarbazide or thiosemicarbazide 24. Acylation of 24 gives 25, whichcan be cyclized upon heating with hydroxide or alkoxide to give thetrisubstituted triazolinone or triazolinethione 26. This approach hasbeen detailed by J. M. Kane and F. P. Miller, U.S. Pat. No. 4,775,688(1988) and G. F. Duffin, J. D. Kendall, and H. R. J. Waddington, J.Chem. Soc., 3799 (1959). Alternative methods of ring closure, such asheating 24 with the orthoester 27, can also be utilized. ##STR28##

In Reaction Scheme I-24, acylation of an aryl- or heteroaryl hydrazinegives 28, which can be reacted with the isocyanate or isothiocyanate 22to yield the 1-acyl-2,4-disubstituted-semicarbazide or--thiosemicarbazide 29. Cyclization of 29 upon heating with hydroxide oralkoxide affords the triazolinone or triazolinethione 30. This chemistryhas been described by H. Gehlen and W. Schade, Liebigs Ann. Chem., 675,180 (1964). ##STR29##

The method of F. Russo, M. Santagati, and G. Pappalardo [Ann. Chim.(Rome), 62, 351 (1972)] (Reaction Scheme I-45) is useful for thesynthesis of trisubstituted triazolinones and triazolinethiones havingbenzylic substituents at N². Treatment of a hydrazide 1 with an aromaticor heteroaromatic aldehyde followed by reduction with sodium borohydridegives the substituted hydrazide 31. Reaction of 31 with the isocyanateor isothiocyanate 22 affords the semicarbazide or thiosemicarbazidederivative 32, which is cyclized to the triazolinone or triazolinethione33 upon heating with hydroxide or alkoxide. ##STR30##

In another approach (Reaction Scheme I-26), imidate 7 is treated with asubstituted hydrazine 23 (especially an aryl or heteroaryl hydrazine) togive the amidrazone 34. Heating 34 with the isocyanate or isothiocyanate22 gives the triazolinone or triazolinethione 26. Syntheses of this typehave been reported by M. Santus, Acta Pol. Pharm., 37, 293 (1980); T.Bany, Rocz. Chem., 42, 247 (1968); and, T. Bany and M. Dobosz, Ann.Univ. Mariae Curie-Sklodowska, Sect. AA, 26/27, 23 (1971). ##STR31##

A route to 2,4,5-trisubstituted 2,4-dihydro-3H-1,2,4-triazol-3-imines(2,4,5-trisubstituted-1,2,4-triazolin-3-(4H) imines) is outlined inReaction Scheme I-27. Reaction of the (arylmethyl)amine 10 with benzoylisothiocyanate (or by other means) gives the substituted thiourea 35,which is methylated to prepare the isothiourea derivative 36. Compound36 can be transformed to the acylaminoguanidine 37 by reacting with thehydrazide 1 or to the aminoguanidine 38 by reacting with hydrazine. Ringclosure of 37 by heating in DMF or cyclization of 38 with carboxylicacid 39 at elevated temperature affords the aminotriazole 40, which canbe separated from the isomer 41. Such pathways have been described by G.J. Durant, G. M. Smith, R. G. W. Spickett, and S. H. B. Wright, J. Med.Chem., 9, 22 (1966) and E. Akerblom, Acta Chem. Scand., 19, 1135 (1965).Finally, alkylation of 40 with the appropriate Ar--CH₂ --Q (where Q is aleaving group such as iodo, bromo, chloro, p-toluenesulfonate, ormethanesulfonate) leads to the triazolinimine 42, which can be separatedfrom any other isomers or by-products formed during the reaction. Thismethod has been described by E. B. Akerblom and D. E. S. Campbell, J.Med. Chem., 16, 312 (1973). ##STR32##

The route shown in Reaction Scheme I-28 utilizes chemistry reported byE. Akerblom, Acta Chem. Scand., 19, 1135 (1965). The substitutedisothiourea 43 is treated with amine 10 to give the aminoguanidinederivative 44. Acylation of 44 with the acid chloride 16 provides theintermediate 45, which can be cyclized by heating with hydroxide oralkoxide. The desired triazolinimine 46 is separated from the isomericproduct 47.

C. Preparation of Pyrimidinones (Formula Ic)

The compounds of Formula Ic wherein either J² or K² is --C(O)-- aresynthesized as illustrated in Schemes I-29 to I-41 below. ##STR33##

Pyrimidinones of formula Ic (wherein J² is --C(O)--) substituted in the1,2,5, and 6-positions may be synthesized as shown in Scheme I-29.Amidines with an R¹ substituent may be reacted with a β-carbonyl esterto give a 4-hydroxypyrimidine. Conversion of the hydroxy group to achloride then to an amine can be achieved by first treating the4-hydroxypyrimidine with POCl₃ then with ammonia.¹ Reaction of the4-aminopyrimidine with the appropriate alkyl halide followed bytreatment with aqueous hydroxide gives the substitutedpyrimidin-4(1H)-one. ##STR34##

Scheme I-30 provides the method by which the isomeric (wherein K² is--C(O)--) 2,3,5, and 6-substituted pyrimidinones may be synthesized. Aβ-carbonyl ester is converted into its corresponding β-aminocrotonatewith ammonia.³ This is then acylated with an R¹ -containing acylchloride (R¹ COCl) and cyclized to a 3,1-oxazin-4-one. When the3,1-oxazin-4-one is reacted with the substituted benzylamine, thedesired fully substituted pyrimidinone 4 results.⁴ ##STR35##

Alternatively, Scheme I-31 shows how an R⁶ imidate may be converted toan amidine with the substituted benzylamine, followed by treatment withan appropriately substituted β-carbonyl ester to give the desiredpyrimidinone 4.⁵ ##STR36##

A third alternative is illustrated in Scheme I-52. A simply amidine canbe reacted with an appropriately substituted β-carbonyl ester to givethe 3-unsubstituted pyrimidinone. This can then be alkylated at the3-position with KOH in methanol (or with NaH in DMF) and theappropriately substituted alkyl halide to give 4. ##STR37##

Scheme I-33 illustrates the general synthesis of pyrimidinones ofFormula Ic in which B is a sulfur atom. Thiourea when condensed with aβ-carbonyl ester gives the 2-thiouracil. This can bebis-trimethylsilylated using hexamethyldisilazane, then alkylatedsequentially on the 1-nitrogen atom and then on the sulfur atom usingchemistry developed by H. Vorbruggen and P. Strehlke.⁶ By this method,one can then obtain compounds of Formula Ic wherein J² is --C(O)-- and Bis a sulfur atom. ##STR38##

The isomeric 2,3-dialkylated thiouracils may be synthesized as shown inScheme I-34. Thiourea can be condensed with an appropriately substitutedβ-carbonyl ester to give the 5,6-disubstituted-2-thiouracil.⁷ This maythen be alkylated sequentially at the sulfur with an R¹ halide, and thenat the nitrogen atom with an appropriately substituted alkyl halide togive the desired tetrasubstituted pyrimidinone 4. ##STR39##

Alternatively, as illustrated in Scheme I-35, an isothiocyanate can beconverted into a thiourea by the addition of ammonia.⁸ This can then becondensed with the appropriately substituted β-carbonyl ester to givethe 3,5,6-trisubstituted-2-thiouracil.⁹ Alkylation at the sulfur atomwith base and an R¹ halide then gives the desired pyrimidinone 4.##STR40##

Scheme I-36 provides a method by which the 2-alkoxy-1-alkylpyrimidinonesmay be synthesized. An appropriately substituted β-keto amide¹⁰ iscyclized with carbonyl diimidazole¹¹ and converted to the correspondinguracil upon treatment with the appropriately substituted primaryamine.¹² The uracil can then be converted to the2-alkoxy-1-alkylpyrimidinone by treatment with an R¹ orthoester.¹³Alternatively, Scheme I-37 shows how the methods of Wittenburg¹⁴ mightbe employed to accomplish the same transformation. ##STR41##

Scheme I-38 shows how the isomeric 2-alkoxy-3-alkylpyrimidinones can beprepared. The primary amine can be converted into an isocyanate¹⁵, thenconverted to the corresponding urea by treatment with ammonia. Reactionof the urea with an appropriately substituted β-keto ester then givesthe 3-substituted uracil.¹⁶ Conversion of the uracil to thecorresponding 2-alkoxy pyrimidinone is achieved using an R¹orthoester.¹⁷ Alternatively, a β-aminocrotonate can be reacted with theisocyanate, as shown in Scheme I-39¹⁸, then alkoxylated with an R¹orthoester.

The β-keto esters used in the preceding schemes can be synthesizedreadily from ethyl hydrogen malonate and an R¹⁷ acid chloride as shownin Scheme I-40.¹⁹ R¹⁷ may be alkyl or aryl. Alkylation of this materialwith an alkyl halide (R¹⁸ -Q) is achieved using sodium hydride in DMSOor by other classical methods. R¹⁸ may be alkyl or aralkyl suitablyprotected, if necessary, so as not to react with NaH.

Scheme I-41 illustrates the preparation of the 5-alkoxycarbonyl moietyand the corresponding 5-amino derivatives. ##STR42## 1. K. Wunsch, A. J.Boulton, Adv. Het. Chem. (1967), 8, 326-9 and references therein.

2. D. J. Brown, E. Hoerger, S. F. Mason, J. Chem. Soc. (1955) 4035.

3. V. Prelog, et al, Ber. (1945) 28 1684.

4. H. B. Kagan, M. Y. H. Suen, Bull. Soc. Chim. Fr. (1966) 1819.

W. Steglich, E. Buschmann, O. Hollitzer, Angew. Chem Int. Ed. Engl.(1974) 13 533.

F. Eiden, B. S. Nagar, Naturwissenschaften (1963) 50 43.

A. Krantz, B. Hoppe, J. Am. Chem. Soc. (1975) 97 6590.

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PART II: Preparation of indole containing analogs and alkylation withthe heterocycles described in Part I.

The 5-methylindole 1a is benzoylated with benzoyl chloride of asubstituted benzoic acid to give N-benzoyl-5-methylindole, 1b. Thebromination of 1b with N-bromosuccinimide and a catalytic amount ofazobisisobutyronitrile in refluxing carbon tetrachloride affordsN-benzoyl-5-bromomethylindole, 1c. ##STR43##

The heterocycle for example, quinazolin-4-one 2a can be alkylated bydeprotonation with sodium hydride and dimethylformamide to give thesodium salt 2bwhich is alkylated with the N-benzoyl-5-bromomethylindole, 1cto afford 2c. ##STR44##

The dihydroindole analog, 3cis prepared by first hydrolyzing theN-benzoyl group of 2cwith 4N sodium hydroxide to give the indole 3a.Treatment of the indole 3awith sodium cyanoborohydride and acetic acidgives the dihydroindole analog 3b. The dihydroindole analog 3bcan beacylated using one of two possible routes both of which use thesubstituted benzoyl chloride: 1) aqueous solution of sodium bicarbonate,dichloromethane or 2) triethylamine, dimethylaminopyridine indichloromethane to give the acylated dihydroindole 3c.

The tetrazole containing analogs 4aare prepared by treatment of thenitrile 2cor 3cwith azido trimethylstannane in toluene at reflux.##STR45##

The indole derivative 3ais acylated either with acid anhydrides or acidchlorides in the presence of NaH in dimethylformamide to afford 5aor 5b.##STR46##

Treatment of the indole derivative, 3awith NaH in dimethylformamide,followed by treatment with isatoic anhydride affords the carbamic acid6. ##STR47##

Treatment of the dihydroindole 3bwith various aldehydes under Streckerconditions produces the cyano compound, 7. ##STR48##

Alkylation of the dihydroindole 3bwith various substituted methylα-bromophenylacetates in the presence of NaH in dimethylforamide affordsthe substituted indole, 8a. Saponification of 8awith aqueous sodiumhydroxide in methanol gives the acid. Treatment of the acid withcarbonyl diimidazole in tetrahydrofuran gives the acylimidazole, whichupon reflux in a THF solution of diazabicycloundecane and theappropriate sulfonamide gives the acylsulfonamide, 8b.

Alkylation of the indole 3awith various aryl bromides in the presence ofNaH in dimethylformamide gives the substituted N benzylindole compound,9. ##STR49##

It will be appreciated by those skilled in the art that functional grouptransformations can be conducted on aryl and heterocyclic rings toafford desired analogs. For example, esters may be converted to amidesby heating them with amines and an amide nitrogen if present in theheterocycle may be alkylated using bases such as sodium hydride in DMFwith the appropriate alkyl halide. Functional group protectionthroughout these syntheses will be chosen to be compatible withsubsequent reaction conditions. Ultimately such protecting groups willbe removed to generate the desired optimally active compounds of FormulaI.

The compounds of this invention form salts with various inorganic andorganic acids and bases which are also within the scope of theinvention. Such salts include ammonium salts, alkali metal salts likesodium and potassium salts, alkaline earth metal salts like the calciumand magnesium salts, salts with organic bases; e.g., dicyclohexylaminesalts, N-methyl-D-glucamine, salts with amino acids like arginine,lysine, and the like. Also, salts with organic and inorganic acids maybe prepared; e.g., HCl, HBr, H₂ SO₄, H₃ PO₄, methanesulfonic,toluenesulfonic, maleic, fumaric, camphorsulfonic. The non toxic,physiologically, acceptable salts are preferred, although other saltsare also useful; e.g., in isolating or purifying the product.

The salts can be formed by conventional means such as by reacting thefree acid or free base forms of the product with one or more equivalentsof the appropriate base or acid in a solvent or medium in which the saltis insoluble, or in a solvent such as water which is then removed invacuo or by freeze drying or by exchanging the cations of an existingsalt for another cation on a suitable ion exchange resin.

Angiotensin II (AII) is a powerful arterial vasoconstrictor, and itexerts its action by interacting with specific receptors present on cellmembranes. The compounds described in the present invention act ascompetitive antagonists of AII at the receptors. In order to identifyAII antagonists and determine their efficacy in vitro, the following twoligand-receptor binding assays were established.

Receptor binding assay using rabbit aortae membrane preparation

Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) weresuspended in 5 mM Tris-0.25M Sucrose, pH 7.4 buffer (50 ml) homogenized,and then centifuged. The mixture was filtered through a cheesecloth andthe supernatant was centrifuged for 30 minutes at 20,000 rpm at 4° C.The pellet thus obtained was resuspended in 30 ml of 50 mM Tris-5 mMMgCl₂ buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mlBacitration and the suspension was used for 100 assay tubes. Samplestested for screening were done in duplicate. To the membrane preparation(0.25 ml) there was added ¹²⁵ I-Sar¹ Ile⁸ -angiotensin II [obtained fromNew England Nuclear] (10 μl; 20,000 cpm) with or without the test sampleand the mixture was incubated at 37° C. for 90 minutes. The mixture wasthen diluted with ice-cold 50 mM Tris 0.9% NaCl, pH 7.4 (4 ml) andfiltered through a glass fiber filter (GF/B Whatman 2.4" diameter). Thefilter was soaked in scintillation cocktail (10 ml) and counted forradioactivity using Packard 2660 Tricarb liquid scintillation counter.The inhibitory concentration (IC₅₀) of potential AII antagonist whichgives 50% displacement of the total specifically bound 125I Sar¹ Ile⁸-angiotensin II was presented as a measure of the efficacy of suchcompounds as AII antagonists.

Receptor assay using Bovine adrenal cortex preparation

Bovine adrenal cortex was selected as the source of AII receptor.Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended inTris.HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate wascentrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded andpellets resuspended in buffer [Na₂ HPO₄ (10 mM)-NaCl (120 mM)-disodiumEDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF)(0.1 mM)].(For screening of compounds, generally duplicates of tubes are used). Tothe membrane preparation (0.5 ml) there was added 3H-angiotensin II (50mM) (10 μl) with or without the test sample and the mixture wasincubated at 37° C. for 1 hour. The mixture was then diluted with Trisbuffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman2.4" diameter). The filter was soaked in scintillation cocktail (10 ml)and counted for radioactivity using Packard 2660 Tricarb liquidscintillation counter. The inhibitory concentration (IC₅₀) of potentialAII antagonist which gives 50% displacement of the total specificallybound ³ H-angiotensin II was presented as a measure of the efficacy ofsuch compounds as AII antagonists.

Using the methodology described above, representative compounds of theinvention were evaluated and were found to exhibit an activity of atleast IC₅₀ <50 μM thereby demonstrating and confirming the utility ofthe compounds of the invention as effective AII antagonists.

The potential antihypertensive effects of the compounds described in thepresent invention may be evaluated using the methodology describedbelow:

Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetizedwith methohexital (Brevital; 50 mg/kg i.p.). The trachea was cannulatedwith PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mmlong) was inserted into the orbit of the right eye and down the spinalcolumn. The rats were immediately placed on a Harvard Rodent Ventilator(rate--60 strokes per minute, volumn--1.1 cc per 100 grams body weight).The right carotid artery was ligated, both left and right vagal nerveswere cut, the left carotid artery was cannulated with PE 50 tubing fordrug administration, and body temperature was maintained at 37° C. by athermostatically controlled heating pad which received input from arectal temperature probe. Atropine (1 mg/kg i.v.) was then administeredand 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes laterantagonists of formula I were administered intravenously or orally.Angiotensin II was then typically given at 5, 10, 15, 30, 45 and 60minute intervals and every half-hour thereafter for as long as the testcompound showed activity. The change in the mean arterial blood pressurewas recorded for each angiotensin II challenge and the percentinhibition of the angiotensin II response was calculated.

Thus, the compounds of the invention are useful in treatinghypertension. They are also of value in the management of acute andchronic congestive heart failure and angina. These compounds may also beexpected to be useful in the treatment of primary and secondaryhyperaldosteronism, renal diseases such as diabetic nephropathy,glomerulonephritis, glomerular sclerosis, nephrotic syndrome,hypertensive nephrosclerosis, end stage renal disease, used in renaltransplant therapy, and to treat renovascular hypertension, scleroderma,left ventricular dysfunction, systolic and diasystolic dysfunction,diabetic retinopathy and in the management of vascular disorders such asmigraine, Raynaud's disease, and as prophylaxis to minimize theatherosclerotic process and neointimal hyperplasia following angioplastyor vascular injury and to retard the onset of the onset of type IIdiabetes. The application of the compounds of this invention for theseand similar disorders will be apparent to those skilled in the art.

The compounds of this invention are also useful to treat elevatedintraocular pressure and to enhance retinal blood flow and can beadministered to patients in need of such treatment with typicalpharmaceutical formulations such as tablets, capsules, injectables andthe like as well as topical ocular formulations in the form ofsolutions, ointments, inserts, gels, and the like. Pharmaceuticalformulations prepared to treat intraocular pressure would typicallycontain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, ofa compound of this invention. For this use, the compounds of thisinvention may also be used in combination with other medications for thetreatment of glaucoma including choline esterase inhibitors such asphysostigmine salicylate or demecarium bromide, parasympathomineticagents such as pilocarpine nitrate, β-adrenergic antagonists such astimolol maleate, adrenergic agonists such as epinephrine and carbonicanhydrase inhibitors such as MK-507.

In the management of hypertension and the clinical conditions notedabove, the compounds of this invention may be utilized in compositionssuch as tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike. The compounds of this invention can be administered to patients(animals and human) in need of such treatment in dosages that willprovide optimal pharmaceutical efficacy. Although the dose will varyfrom patient to patient depending upon the nature and severity ofdisease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize, the dosage range will generally be about 1 to1000 mg. per patient per day which can be administered in single ormultiple doses. Perferably, the dosage range will be about 5 to 500 mg.per patient per day; more preferably about 5 to 300 mg. per patient perday.

The compounds of this invention can also be administered in combinationwith other antihypertensives and/or diuretics. For example, thecompounds of this invention can be given in combination with diureticssuch as hydrochlorothiazide, chlorothiazide, chlorothalidone,methyclothiazide, furosemide, ethacrynic acid, triamterene, amiloride,atriopeptin and spironolactone; calcium channel blockers, such asdiltiazem, felodipine, nifedipine, amlodipine, nimodipine, isradipine,nitrendipine and verapamil; β-adrenergic antagonists such as timolol,atenolol, metoprolol, propanolol, nadolol and pindolol; angiotensinconverting enzyme inhibitors such as enalapril, lisinopril, captopril,ramipril, quinapril and zofenopril; renin inhibitors such as A-69729, FK906 and FK 744; β-adrenergic antagonists such as prazosin, doxazosin,and terazosin; sympatholytic agents such as methyldopa, (alone or withANP) clonidine and guanabenz, atriopeptidase inhibitors (alone or withANP) such as UK-79300; serotonin antagonists such as ketanserin; A₂-adenosine receptor agonists such as CGS 22492C; potassium channelagonists such as pinacidil and cromakalim; and various otherantihypertensive drugs including reserpine, minoxidil, guanethidine,hydralazine hydrochloride and sodium nitroprusside as well ascombinations of the above-named drugs s well as admixtures andcombinations thereof.

Combinations useful in the management of congestive heart failureinclude, in addition, compounds of this invention with cardiacstimulants such as dobutamine and xamoterol and phosphodiesteraseinhibitors including amrinone and mirinone.

Typically, the individual daily dosages for these combinations can rangefrom about one fifth of the minimally recommended clinical dosages tothe maximum recommended levels for the entities when they are givensingly.

To illustrate these combinations, one of the angiotensin II antagonistsof this invention effective clinically in the 5-500 milligrams per dayrange can be effectively combined at levels at the 1.0-500 milligramsper day range with the following compounds at the indicated per day doserange: hydrochlorothiazide (6-100 mg) chlorothiazide (125-500 mg),ethacrynic acid (5-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),propranolol (10-480 mg), timolol maleate (1-20 mg.), methyldopa(125-2000 mg), felodipine (1-20 mg), nifedipine (5-120 mg), nitrendipine(5-60 mg) and diltiazem (30-540 mg). In addition, triple drugcombinations of hydrochlorothiazide (5-100 mg) plus amiloride (5-20 mg)plus angiotensin II antagonist of this invention (1-500 mg) orhydrochlorothiazide (5-100 mg) plus timolol maleate (5-60) plus anangiotensin II antagonist of this invention (1-500 mg) orhydrochlorothiazide (5-200 mg) and nifedipine (5-60 mg) plus anangiotensin II antagonist of this invention (1-500 mg) are effectivecombinations to control blood pressure in hypertensive patients.Naturally, these dose ranges can be adjusted on a unit basis asnecessary to permit divided daily dosage and, as noted above, the dosewill vary depending on the nature and severity of the disease, weight ofpatient, special diets and other factors.

Typically, these combinations can be formulated into pharmaceuticalcompositions as discussed below.

About 1 to 100 mg. of compound or mixture of compounds of Formula I or aphysiologically acceptable salt is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, flavor, etc., in a unit dosage form as called for byaccepted pharmaceutical practice. The amount of active substance inthese compositions or preparations is such that a suitable dosage in therange indicated is obtained.

Illustrative of the adjuvants which can be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asmicrocrystalline cellulose; a disintegrating agent such as corn starch,pregelatinized starch, alginic acid and the like; a lubricant such asmagnesium stearate; a sweetening agent such as sucrose, lactose orsaccharin; a flavoring agent such as peppermint, oil of wintergreen orcherry. When the dosage unitform is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier such as fattyoil. Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccuring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccuring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

The compounds of this invention are also useful to treat elevatedintraocular pressure and can be administered to patients in need of suchtreatment with typical pharmaceutical formulations such as tablets,capsules, injectables, as well as topical ocular formulations in theform of solutions, ointments, inserts, gels and the like. Pharmaceuticalformulations prepared to treat intraocular pressure would typicallycontain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% byweight of a compound of this invention.

Thus, the compounds of the invention are useful in treatinghypertension. They are also of value in the management of acute andchronic congestive heart failure, in the treatment of secondaryhyperaldosteronism, primary and secondary pulmonary hypertension, renalfailure such as diabetic nephropathy, glomerulonephritis, scleroderma,and the like, renal vascular hypertension, left ventricular dysfunction,diabetic retinopathy, and in the management of vascular disorders suchas migraine or Raynaud's disease. The application of the compounds ofthis invention for these and similar disorders will be apparent to thoseskilled in the art.

The useful central nervous system (CNS) activities of the compounds ofthis invention are demonstrated and exemplified by the ensuing assays.

COGNITIVE FUNCTION ASSAY

The efficacy of these compounds to enhance cognitive function can bedemonstrated in a rat passive avoidance assay in which cholinomimeticssuch as physostigmine and nootropic agents are known to be active. Inthis assay, rats are trained to inhibit their natural tendency to enterdark areas. The test apparatus used consists of two chambers, one ofwhich is brightly illuminated and the other is dark. Rats are placed inthe illuminated chamber and the elapsed time it takes for them to enterthe darkened chamber is recorded. On entering the dark chamber, theyreceive a brief electric shock to the feet. The test animals arepretreated with 0.2 mg/kg of the muscarinic antagonist scopolamine whichdisrupts learning or are treated with scopolamine and the compound whichis to be tested for possible reversal of the scopolamine effect. Twentyfour hours later, the rats are returned to the illuminated chamber. Uponreturn to the illuminated chamber, normal young rats who have beensubjected to this training and who have been treated only with controlvehicle take longer to re-enter the dark chamber than test animals whohave been exposed to the apparatus but who have not received a shock.Rats treated with scopolamine before training do not show thishesitation when tested 24 hours later. Efficacious test compounds canovercome the disruptive effect on learning which scopolamine produces.Typically, compounds of this invention should be efficacious in thispassive avoidance assay in the dose range of from about 0.1 mg/kg toabout 100 mg/kg.

ANXIOLYTIC ASSAY

The anxiclytic activity of the invention compounds can be demonstratedin a conditioned emotional response (CER) assay. Diazepam is aclinically useful anxiolytic which is active in this assay. In the CERprotocol, male Sprague Dawley rats (250-350 g) are trained to press alever on a variable interval (VI) 60 second schedule for foodreinforcement in a standard operant chamber over weekly (five days perweek) training sessions. All animals then receive daily 20 minuteconditioning sessions, each session partitioned into alternating 5minute light (L) and 2 minute dark (D) periods in a fixed L1D1L2D2L3sequence. During both periods (L or D), pressing a lever delivers foodpellets on a VI 60 second schedule: in the dark (D), lever presses alsoelicit mild footshock (0.8 mA, 0.5 sec) on an independent shockpresentation schedule of VI 20 seconds. Lever pressing is suppressedduring the dark periods reflecting the formation of a conditionedemotional response (CER).

Drug testing in this paradigm is carried out under extinctionconditions. During extinction, animals learn that responding for food inthe dark is no longer punished by shock. Therefore, response ratesgradually increase in the dark periods and animals treated with ananxiolytic drug show a more rapid increase in response rate than vehicletreated animals. Compounds of this invention should be efficacious inthis test procedure in the range of from about 0.1 mg/kg to about 100mg/kg.

DEPRESSION ASSAY

The antidepressant activity of the compounds of this invention can bedemonstrated in a tail suspension test using mice. A clinically usefulantidepressant which serves as a positive control in this assay isdesipramine. The method is based on the observations that a mousesuspended by the tail shows alternate periods of agitation andimmobility and that antidepressants modify the balance between these twoforms of behavior in favor of agitation. Periods of immobility in a 5minute test period are recorded using a keypad linked to a microcomputerwhich allows the experimenter to assign to each animal an identity codeand to measure latency, duration and frequency of immobile periods.Compounds of this invention should be efficacious in this test procedurein the range of from about 0.1 mg/kg to about 100 mg/kg.

SCHIZOPHRENIA ASSAY

The antidopaminergic activity of the compounds of this invention can bedemonstrated in an apomorphine-induced sterotypy model. A clinicallyuseful antipsychotic drug that is used as a positive control in thisassay is haloperidol. The assay method is based upon the observationthat stimulation of the dopaminergic system in rats produces stereotypedmotor behavior. There is a strong correlation between the effectivenessof classical neuroleptic drugs to block apomorphine induced stereotypyand to prevent schizophrenic symptoms. Stereotyped behavior induced byapomorphine, with and without pretreatment with test compounds, isrecorded using a keypad linked to a microcomputer. Compounds of theinvention should be efficacious in this assay in the range of from about0.1 mg/kg to about 100 mg/kg.

In the treatment of the clinical conditions noted above, the compoundsof this invention may be utilized in compositions such as tablets,capsules or elixirs for oral administration, suppositories for rectaladministration, sterile solutions or suspensions for parenteral orintramuscular administration, and the like. The compounds of thisinvention can be administered to patients (animals and human) in need ofsuch treatment in dosages that will provide optimal pharmaceuticalefficacy Although the dose will vary from patient to patient dependingupon the nature and severity of disease, the patient's weight, specialdiets then being followed by a patient, concurrent medication, and otherfactors which those skilled in the art will recognize, the dosage rangewill generally be about 5 to 6000 mg. per patient per day which can beadministered in single or multiple doses. Perferably, the dosage rangewill be about 10 to 4000 mg. per patient per day; more preferably about20 to 2000 mg. per patient per day.

In order to obtain maximal enhancement of cognitive function, thecompounds of this invention may be combined with other cognitionenhancing agents. These include acetylcholinesterase inhibitors such asheptylphysostigmine and tetrahydroacridine (THA; tacrine), muscarinicagonists such as oxotremorine, inhibitors of angiotensin convertingenzyme such as octylramipril, captopril, ceranapril, enalapril,lisinopril, fosinopril and zofenopril, centrally-acting calcium channelblockers and as nimodipine, and nootropic agents such as piracetam.

In order to achieve optimal anxiolytic activity, the compounds of thisinvention may be combined with other anxiolytic agents such asalprazolam, lorazepam, diazepam, and busipirone.

In order to achieve optimal antidepressant activity, combinations of thecompounds of this invention with other antidepressants are of use. Theseinclude tricyclic antidepressants such as nortriptyline, amitryptylineand trazodone, and monoamine oxidase inhibitors such as tranylcypromine.

In order to obtain maximal antipsychotic activity, the compounds of thisinvention may be combined with other antipsychotic agents such aspromethazine, fluphenazine and haloperidol.

The following examples illustrate the preparation of the compounds ofFormula I and their incorporation into pharmaceutical compositions andas such are not to be considered as limiting the invention set forth inthe claims appended hereto.

PREPARATION OF 2-ALKYL-QUINAZOLIN-4-(1H)-ONES EXAMPLE 12-Butyl-6-methylquinazolin-4(1H)-one

To a solution of 3.0 g (20 mmol) of 2-amino-5-methylbenzoic acid in 20mL of dry DMF at 0° C. was added 200 mg of DMAP followed by 6.07 g (60mmol) of triethyl amine and 5.02 g (40 mmol) of valeryl chloride. Theresulting mixture was stirred at 0° C. for 30 minutes. The mixture washeated to 110° C. and monitored by TLC for the formation of theintermediate quinoxazolone (rf=0.8, 40% EtOAc/ hexane). Followingcomplete formation of the intermediate 10 g (100 mmol) of NH₄ CO₃ wasadded cautiously. Heating was continued to ensure consumption of thequinoxazolone and formation of the polar (rf=0.4, 40%EtOAc/hexane)quinazolin-4(1H)-one. The reaction mixture was concentrated in vacuo andthe residue was taken up in 50 mL of ether and 50 mL of water. Themixture was filtered and the filtrate discarded after washing theresidue with 20 mL of ether. The residue was recrystallized from MeOH togive 1.07 g (5 mmol) of a white crystaline solid. 25% yield overall. ¹H-NMR (CDCl₃): 0.94 (t, 3H, J=6.7 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.49(s, 3H), 2.78 (t, 2H), 7.60 (m, 2H), 8.05 (m, 1H). Anal (C₁₃ H₁₆ N₂ O),C, H, N.

EXAMPLE 2 6-Methyl-2-propylquinazoline-4(1H)-one

The 2 propyl derivative was prepared in the identical fashion as the2-butyl derivative through the use of butyryl chloride in place ofvaleryl chloride. The product was recrystallized from hexane/acetone togive white crystals. 32% yield. ¹ H-NMR (CDCl₃): 11.51 (bs, 1H), 8.08(s, 1H), 7.60 (s, 2H), 2.78 (3 line m, 2H), 2.01 (s, 3H), 1.92 (m, H),1.09 (t, 3H).

EXAMPLE 3 2-Butyl-7-methylquinazoline-4(1H) one

Same procedure as in Example 1 with valeroyl chloride and2-amino-4-methylbenzoic acid. The product was recrystallized from MeOHrecovering 0.91 g (4.2 mmol). 21% yield overall. ¹ H-NMR (CDCl₃): 0.99(t, 3H, J=7.4 Hz), 1.49 (m, 2H), 1.86 (m, 2H), 2.50 (s, 3H), 2.76 (t,2H, J=7.81 Hz), 7.28 (d, 1H, J=8.3 Hz), 7.49 (s, 1H), 8.15 (d, 1H, J=8.3Hz). Anal (C₁₃ H₁₆ N₂ O), C, H, N.

EXAMPLE 4 2-Butyl-naphtho[2,3-e]quinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-aminonapthoic acid. Product was recrystallized from MeOH. Acontaminant co-crystallizes with the desired product. The contaminant is25% of the product by ¹ H-NMR. Recovered 1.6 g (59% yield). ¹ H-NMR(CDCl₃): 0.97 (t, 3H, J=7.3 Hz), 1.42 (m, 2H), 1.75 (m, 2H), 2.48 (t,2H, J=7.4 Hz), 7.42 (t, 1H, J=7.8 Hz), 7.54 (t, 1H, J=8.3 Hz), 7.77 (d,1H, J=7.8 Hz), 7.82 (d, 1H, J=8.31 Hz),8.07 (s, 1H), 9.08 (s, 1H), 10.89(bs, 1H).

EXAMPLE 5 2-Butyl-5-methylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-6-methylbenzoic acid on a 16 mmol scale. The concentratedreaction mixture was diluted with 50 mL ether and 50 mL H₂ O. Themixture was agitated for several minutes and then filtered in vacuo. Onfiltration further crystalline material formed in the filtrate. Thefiltrate was filtered again. This procedure was repeated a further twotimes. The precipitates were collected and combined. The ethereal phasewas decanted from the aqueous Phase, and concentrated to 15 mL. 25 mL ofhexanes was then added and the mixture filtered. The combinedprecipitates were recrystallized from MeOH/H₂ O to give 0.73 g (3.37mmol) of fluffy white crystals. 21% yield. 1H-NMR (CDCl₃): 0.98 (t, 3H,J=7.38 Hz), 1.48 (m, 2H), 1.87 (m, 2H), 2.75 (dd, 2H, J=8.09 Hz), 2.89(s, 3H), 7.20 (d, 1H, J=6.73 Hz), 7.56 (m, 2H), 11.68 (bs, 1H).

EXAMPLE 6 2-Butyl-6,8-dimethylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-5,8-dimethylbenzoic acid on a 12 mmol scale. The productcollected from filtration of the ether/water mixture was recrystalizedfrom MeOH. ¹ H-NMR and TLC indicated that the product isolated was a 50%mixture of the desired quinazoline and a contaminant. An aliquot of 0.5g of this material was concentrated onto 5 mL of flash silica andapplied to the surface of a flash chromatography column. The column waseluted with 60% EtOAc/hexanes. The first eluted compound (0.14 g) wascollected as a TLC homogeneous sample of the desired product. 1H NMR(CDCl₃): 0.99 (t, 3H, J=7.32 Hz), 1.48 (m, 2H), 1.85 (m, 2H), 2.44 (s,3H), 2.58 (s, 3H), 2.75 (dd, 2H, J=7.87,7.87 Hz), 7.43 (s, 1H), 7.91 (s,1H), 10.70 (bs, 1H).

EXAMPLE 7 2-Butyl-8-methylquinazoline-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-6-methylbenzoic acid on a 1 mmol scale. The concentratedreaction mixture was diluted with 20 mL ether/20 mL H₂ O. The mixturewas filtered. The ethereal phase was seperated, dried (MgSO₄), filteredand concentrated. The residue was flash chromatographed over silicaeluting with 50% EtOAc/hexanes to give rise to 48 mg (0.22 mmol) of afluffy yellow solid. 22% yield. ¹ H-NMR (CDCl₃): 1.02 (t, 3H), 1.52 (m,2H), 1.88 (m, 2H), 2.62 (s, 3H), 2.79 (dd, 2H), 7.35 (dd, 1H), 7.61 (d,1H), 8.12 (d, 1H). FABMS: 217 (M⁺ +1) calc for C₁₃ H₁₆ N₂ O.

EXAMPLE 8 2-Butyl-6-isopropylquinazolin-4(1H)-one

Same procedure as in Example 1 with valeroyl chloride and2-amino-5-isopropylbenzoic acid on a 16 mmol scale. The concentratedreaction mixture was partitioned between 20 mL water and 20 mL of ether.A fine white precipitate was removed by filtration and recrystallizedfrom MeOH/water. The first crop gave rise to 0.56 g of fluffy whitecrystals. ¹ H-NMR (CDCl₃): 0.99 (t, 3H, J=7.3 Hz), 1.32 (d, 6H, J=6.89Hz), 1.48 (m, 2H), 1.85 (m, 2H), 2.77 (3 line m, 2H, J=7.9 Hz), 3.06 (m,1H), 7.65 (m, 2H), 8.11 (s, 1H), 11.22 (bs, 1H). FABMS: 245 (M⁺ +1) calcfor C₁₅ H₂₀ N₂ O.

EXAMPLE 9 2-Butyl-6-thiomethylquinazolin-4(1H)-one

Same procedure as that described in Example 1. However on addition ofether/water to the reaction mixture a precipitate of the quinazolinonewas not formed. The aqueous phase was extracted with ether and thecombined ethereal extracts were washed with brine and dried over MgSO₄.The mixture was filtered and concentrated in vacuo to give a mixture ofthe desired product and 2-(N-valeroyl amino)-5-thiomethylbenzamide. Thismixture was heated with 2 equivalents of 1N NaOH solution in water at100° C. until a clear solution was obtained. The solution was cooled,acidified, and filtered to give a pale yellow precipitate. The productwas recrystalized from MeOH to give a 73% overall yield of the titlecompound 1H NMR (CDCl₃ -300 MHz): 1.00 (t, 3H, J=7.3 Hz), 1.50 (m, 2H),1.86 (m, 2H), 2.58 (s, 3H), 2.76 (3 line m, 2H, J=7.9 Hz), 7.62 (m, 2H),8.03 (d, 1H, J=1.9 Hz), 11.11 (bs, 1H).

EXAMPLE 10 2-Butyl-6-nitroquinazolin-4(1H)-one

To a mixture of 326 mg (2 mmol) of 2-cyano-4-nitroaniline in 10 mL ofCH₂ Cl₂ at 0° C. was added 0.34 mL (2.4 mmol) of triethylamine and 25 mgof DMAP. To this mixture was added 0.26 ml of valeryl chloride dropwise.The reaction mixture was allowed to warm to room temperature over 1.5hours and then concentrated in vacuo. The residue was dissolved in 40 mlof EtOAc and washed with 25 ml of water, 25 ml of saturated NaHCO₃ and25 ml of brine. The organic phase was dried over Na₂ SO₄, filtered andconcentrated. The residue (0.46 g) was purified by flash chromatography.The residue was absorbed onto 0.6 g of silica which was applied to thesurface of a 5.5"×0.75" silica flash chromatography column. The productwas eluted with 20% EtOAc/hexanes to give 0.21 g ofN-valeryl-2-cyano-4-nitro-anilide (44% yield). 0.1 g (0.42 mmol) of theamide was dissolved in 1.5 mL of MeOH. To this solution was added 138 μLof a 30% hydrogen peroxide solution followed by 330 μL of a 3N NaOHsolution. The solution was refluxed for 1.5 hours, cooled andconcentrated in vacuo. The residue was dissolved in 10 mL of water.Dropwise addition of a saturated solution of NH₄ Cl caused the productto precipitate out as 90 mg (0.36 mmol) of a yellow powder. (87% yield.¹ H-NMR (CDCl₃): 1.02 (t, 3H, J=7.32 Hz), 1.52 (m, 2H), 1.90 (m, 2H),2.82 (dd, 2H, J=8.03 Hz), 7.82 (d, 1H, J=9.01 Hz), 8.56 (dd, 1H, J=2.6,8.9 Hz), 9.14 (d, 1H, J=2.71 Hz).

EXAMPLE 11 2-Butylquinazolin-4(1H)-one

To a solution of 500 mg 2-aminobenzonitrile (4.23 mmol), 514 mgtriethylamine (5.08 mmol), and 50 mg DMAP (0.41 mmol) in 6 mL CH₂ Cl₂ at0° C. was added 562 mg valeryl chloride (4.66 mmol) dropwise over 1minute. The mixture was warmed to room temperature and stirred fortwenty minutes. The mixture was then diluted with water and brine andthen was extracted three times with ether. The combined organic materialwas dried over MgSO₄, stripped of solvent in vacuo, and was purified byflash chromatography eluting with 20% ethyl acetate in hexane to give2-valerylamido-benzonitrile. R_(f) 0.22 in 20% ethyl acetate in hexane.¹ H-NMR (300 MHz, CDCl₃): 8.42 (d, 1H), 7.60-7.10 (m, 2H), 6.72 (m, 1H),4.40 (br s, 1H), 2.46 (t, 2H), 1.74 (m, 2H), 1.43 (m, 2H), 0.97 (t, 3H).

To a solution of 5.1 g of the amide in 90 mL methanol were added 21 mL3N NaOH and 10 ml 30% H₂ O₂ at room temperature. The mixture wasrefluxed for 30 minutes and concentrated in vacuo. Water and sat. NH₄ Clwas added and the mixture extracted 3 times with ether. The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo and the residue was recrystallized from hexane/acetone to give twocrops of the product as white needles. 2.2 g, 43% yield. R_(f) : 0.16 in20% EtOAc in CH₂ Cl₂. ¹ H-NMR (CDCl₃): 8.29 (m, 1H), 7.81-7.68 (m, 2H),7.47 (m, 1H), 2.79 (3 line m, 2H), 1.87 (m, 2H), 1.51 (m, 2H), 1.00 (t,1H).

EXAMPLE 12 6-Bromomethyl-2-butylquinazolin-4(1H)-one

To a suspension of 2.6 g (12 mmol) of the product of Example 2 in 100 mLof dry CCl₄ was added 2.56 g of N-bromosuccinimide followed by 200 mg ofbenzoyl peroxide. The reaction mixture was heated to reflux for 45minutes at which time a precipitate formed throughout. The reactionmixture was concentrated in vacuo and the residue partitioned between150 mL of EtOAc and 100 mL of water. The mixture was shaken and thenfiltered to give 1.59 g of the title compound (45% yield). The filtratewas seperated into two phases and the organic phases was washed with 75mL of sat. NaHCO₃ solution followed by 75 mL of water and 75 mL ofbrine. The organic phase was dried over MgSO₄, filtered and the filtratewas concentrated in vacuo. The residue was purified by recrystalizationfrom EtOAc to give 0.52 g (1.76 mmol) of the same product as wasrecovered above. Total yield 60%. ¹ H-NMR (CDCl₃): 1.00 (t, 3H, J=7.33Hz), 1.49 (m, 2H), 1.84 (m, 2H), 2.77 (3 line m, 2H, J=7.7 Hz), 4.61 (s,2H), 7.68 (d, 1H, J=8.4 Hz), 7.80 (dd, 1H, J=8.4, 2.1 Hz), 8.27 (d, 1H,J=2.1 Hz), 11.02 (bs, 1H).

EXAMPLE 13 5-Bromomethyl-2-butylquinazolin-4(1H)-one

The product of Example 5 was treated as in Example 13 to give a 71%yield of a white solid. ¹ H-NMR (CDCl₃) 1.0 (t, 3H, J=7.3 Hz), 1.53 (m,2H), 2.90 (m, 2H), 2.81 (3 line m, 2H, J=7.98 Hz), 5.31 (s, 2H), 7.45(m, 1H), 7.71 (m, 2H), 11.28 (bs, 1H).

EXAMPLE 14 6-Acetoxymethyl-2-butylquinazolin-4(1H)-one

To a solution of 2.1 g (7.0 mmol) of the quinazolinone prepared inExample 12 in 15 mL of dry DMF was added 1.74 g (20.0 mmol) of sodiumacetate. The mixture was heated to 60° C. for 3 hours. The reactionmixture was concentrated in vacuo and the residue dissolved in 100 mL ofCH₂ Cl₂. The solution was washed with water (3×20 mL), brine (1×20 mL)and dried over MgSO₄. The mixture was filtered and concentrated invacuo. The residue was recrystallized from MeOH/H₂ O to give 1.31 g (4.8mmol) of a colorless solid. 68% yield. ¹ H-NMR (CDCl₃): 0.99 (t, 3H,J=7.32 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.14 (t, 3H), 2.77 (3 line m,2H, J=7.71 Hz), 5.23 (s, 2H), 7.69-7.78 (m, 2H), 8.25 (s, 1H), 10.90(bs, 2H).

EXAMPLE 15 5-Acetoxymethyl-2-butylquinazolin-4(1H)-one

The product of Example 13 was treated as in Example 14 to give afterrecrystallization from EtOAc a 77% yield of the desired acetylatedproduct. ¹ H-NMR (CDCl₃): 0.98 (t, 3H, J=7.38 Hz), 1.50 (m, 2H), 1.88(m, 2H), 2.19 (s, 3H), 2.77 (3 line m, 2H, J=7.93 Hz), 5.85 (s, 2H),7.48 (m, 1H), 7.70 (m, 2H), 11.65 (bs, 1H).

EXAMPLE 16 6-Nitro-2-propylquinazolin-4(1H)-one.

To a solution of 16.3 g (0.1 mol) of 2-amino-5-nitrobenzonitrile in 200ml of CH₂ Cl₂ at 0° C. was added 21 ml (0.15 mol) of triethyl aminefollowed by 0.3 g of DMAP and 11.71 g (0.11 mol) of butyryl chloride.The reaction mixture was warmed to room temperature and then heated overnight at 50° C. The solution was washed with 1N HCl (1×20 ml), water(1×20 ml), saturated NaHCO₃ (2×20 ml) and brine (1×20 ml) and dried overMgSO₄. The solution was filtered and concentrated in vacuo. The residuewas dissolved in 200 ml of MeOH to which was added 44 ml (0.22 mol) of5M NaOH solution followed by the dropwise addition of 25 ml (0.22 mol)30% H₂ O₂ and 50 ml of water. The mixture was refuxed for 4 hours,cooled and filtered. The filtrate was acidified with 1N HCl and theresulting precipitate recovered by filtration. The residue wasrecrystalized from MeOH to give 8.3 g (0.036 mol) of pale brown fluffycrystals. 36% yield. 1H NMR (CDCl₃): 1.10 (t, 3H, J=7.4 Hz), 1.93 (m,2H), 2.79 (3 line m, 2H, J=7.3 Hz), 7.80 (d, 1H, J=8.9 Hz), 8.55 (dd,1H, J=2.5, 8.8 Hz), 9.14 (bs, 1H).

PREPARATION OF 5-ALKYL-2-ARYL-2,4-DIHYDRO-3H-1,2,4-TRIAZOL-3-ONE EXAMPLE17 5-Butyl-2-(2-chlorophenyl)-5-Butyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Step A: Preparation of ethyl valerimidate (Free Base)

A 12.7 g (76.7 mmol) sample of ethyl valerimidate hydrochloride(prepared from valeronitrile, ethanol, and hydrogen chloride gas asdescribed by A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 1926, 48,734) was dissolved in 33% (w/w) potassium carbonate solution (made bydissolving 15 g of K₂ CO₃ in 30 mL of H₂ O) and immediately extractedwith either (3×40 mL). The combined ether layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give 7.09 g (72%) of theproduct as a clear oil, which was used directly in the next step. ¹ HNMR (300 MHz, CDCl₃, ppm): δ 0.88 (t, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 3H),1.31 (m, 2H), 1.50 (m, 2H), 2.19 (t, J=7.5 Hz, 2H), 4.06 (q. J=7 Hz,2H), 6.84 (br s, 1H).

Step B: Preparation of ethyl N-carbethoxyvalerimidate

A solution of 6.5 g (50.3 mmol) of ethyl valerimidate (free base) in 90mL of dry CH₂ Cl₂ was treated with 7.71 mL (5.60 g, 55.3 mmol) oftriethylamine. The resulting solution was stirred under N₂ at -10° C. inan ice salt bath as a solution of 4.81 mL (5.46 g, 50.3 mmol) of ethylchloroformate in 10 mL of CH₂ Cl₂ was added dropwise over 25 minutes.Upon completion of the addition, the cooling bath was removed, and themixture was stirred at room temperature for 2 hours. Next, the solventwas removed by evaporation in vacuo. The residue was taken up in hexaneand filtered to remove triethylamine hydrochloride. Concentration of thefiltrate yielded 7.08 g (70%) of the product as a yellow oil, suitablefor use in the next step without further purification. NMR indicated amixture of syn and anti isomers. TLC (98:2 CH₂ Cl₂ -MeOH) showed a closepair of spots, R_(f) 0.48, 0.52. ¹ H NMR (200 MHz, CDCl₃, ppm): δ 0.86(distorted t, J=7.5 Hz, 3H), 2.15-2.35 (m, 8H), 2.4- 2.65 (m, 2H), 2.19,2.35 (t, J=7.5 Hz, 2H total), 4.0-4.2 (m, 4H). EI-MS: m/e 201 (M⁺).

Step C: Preparation of5-butyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of 285 mg (2 mmol) of (2-chlorophenyl)hydrazine (generatedfrom the hydrochloride by partitioning between ether and 1N Na₂ CO₃) in3 mL of toluene was added 442 mg (2.2 mmol) of ethylN-carboethoxyvalerimidate (Example 4 Step B). The mixture was heated at45°-50° C. for 45 minutes. At this time the mixture was treated with 307mL (223 mg, 2.2 mmol) of triethylamine and then heated overnight at 95°C. The mixture was cooled and concentrated in vacuo. Flashchromatography of the residue on silica gel (gradient elution with0.6-2% methanol in CH₂ Cl₂) gave 257 mg (51%) of the product as an offwhite solid, mp 103°-104° C., homogeneous by TLC in 19:1 CH₂ Cl₂ -MeOH.

¹ H NMR (200 MHz, CDCl₃, ppm): δ 0.92 (t, J=7 Hz, 3H), 1.38 (m, 2H),1.68 (m, 2H), 2.57 (t, J=7.5 Hz, 2H), 7.3-7.55 (m, 4H), 12.04 (br s,1H).

FAB-MS: m/e 252 (M+1).

Analysis for C₁₂ H₁₄ ClN₃ O Calcd: C, 57.26; H, 5.61; N, 16.69 Found: C,57.31; H, 5.69, N, 16.58

PREPARATION OF 5,6 DIALKYL PYRIMIDIN-4(3H)-ONE EXAMPLE 182-n-Butyl-5-ethyl-6-methylpyrimidin-4(3H)-one

A solution of 3.0 g valeramidine hydrochloride, 3.47 g ethyl-2ethylacetoacetate, and 5.8 mL triethylamine in 20 mL DMF was heated to120° C. for 18 hours. The mixture was diluted with brine and extractedthree times with ether. The combined organic material was washed withbrine, was dried over MgSO₄, was stripped of solvent in vacuo, and thenwas still flash chromatographed in 3% MeOH in CH₂ Cl₂ to give the titlecompound as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ 2.62 (3 line m, 2H), 2.51 (4 line m, 2H),2.32 (s, 3H), 1.75 (m, 2H), 1.42 (6 line m, 2H), 1.10 (3 line m, 3H),0.95 (3 line m, 3H).

EXAMPLE 19 2-n-Butyl-5,6-dimethylpyrimidin-4(3H)-one

The title compound is prepared using the procedure in Example 18 andethyl-2-methyl-acetoacetate in place of ethyl 2-ethylacetoacetate.

PREPARATION OF 3-N-ALKYL-2-ALKYLQUINAZOLIN-4(3H)-ONES

A general procedure for the synthesis of3-N-akylated-quinazolin-4(3H)-ones is given below.

A suspension of 1.1 mmol of NaH in 2 mL of dry DMF at 0° C. undernitrogen is treated with 1 mmol of the quinazolin-4(1H)-one as a solid(most quinazolin-4(1H)-ones prepared were insoluble in DMF). Immediateevolution of hydrogen could be observed as the quinazolin-4(1H)-one isdeprotonated and dissolves. After 30 minutes the solution was warmed toroom temperature for a further 30 minutes. To this solution cooled to 0°C. is added a solution of 1 mmol of the appropriate bromomethylphenyl/methanesulfonylmethylphenyl thiophene, benzothiophene or furan, asprepared below, in 1.5 mL of DMF. After 30 minutes, the reaction mixtureis warmed to room temperature and stirred overnight. The solution isconcentrated in vacuo, and the residue dissolved in 50 mL of EtOAc. Thesolution is washed with water (3×10 mL) and brine (2×10 mL). The organicphase is dried over MgSO₄, filtered and concentrated in vacuo. Theresidue is then chromatographed on a silica gel column.

The procedure herein described can be used to generate5-alkyl-2-aryl-3-N-alkyl-'2,4-dihydro-1,2,4-triazol-3-ones and2,5,6-trialkyl-3-N-alkylpyrimidin-4-(3H)-one. The general procedures forpreparing the substituted indoles and dihydroindoles are described belowusing 2-butyl-6-methylquinazolin-4-(1H)-ones:

EXAMPLE 203-(N-Benzoyl-5-indolyl)methyl-2-butyl-6-methyl-3H-quinazolin-4-one

Step A: Preparation of N-benzoyl-5-methylindole

To a solution of 5-methylindole (1.0 g, 7.6 mmol) in 8.0 mL of CH₂ Cl₂was added N,N-dimethylamino pyridine (0.186 g, 1.52 mmol), 2.12 mL(15.24 mmol) of triethylamine and 0.97 mL (1.18 g, 8.39 mmol) of benzoylchloride. The resulting solution was stirred for 16 hours at roomtemperature. The solution was diluted with 500 mL of CH₂ Cl₂ and washedwith 200 mL of saturated aqueous NaHCO₃ and 200 mL of brine. The organicphase was dried over MgSO₄, filtered, and concentrated to a yellow oil.The resultant oil was flash chromatographed eluting with 20% ethylacetate in hexane yielding 1.73 g (96%) of the titled compound as awhite powder.

FAB-MS: m/e=236 (M+1)

¹ H-NMR (300 MHz, CDCl₃, ppm) d 8.29 (d, 1H); 7.71 (d, 2H); 7.56 (d,1H); 7.51 (d, 2H); 7.38 (s, 1H); 7.24 (d, 1H); 7.20 (d, 1H); 6.53 (d,2H); 2.47 (s, 3H).

Step B: Preparation of N-benzoyl-5-(bromomethyl)-indole

A suspension of the product of Step A (5.5 g 23.4 mmol) in 10 mL of CCl₄was heated to reflux. N-bromosuccinimide (4.6 g, 25.7 mmol) and severalcrystals (approximately 100 mg) of azoisobutyronitrile (AIBN) wereadded. The resultant solution was stirred at reflux for 4 hours. Thesolution was cooled, diluted with 1.5 L of CH₂ Cl₂ and washed with 400mL of H₂ O and 400 mL of brine. The organic phase was dried over MgSO₄,filtered and concentrated to a brown oil. The resultant oil was flashchromatographed eluting with 10:1 hexane/ethyl acetate to afford thetitled compound (5.6g, 80%) as a yellow powder.

FAB-MS: m/e=314 (M+1)

¹ H NMR (300 MHz, CDCl₃, Ppm) d 8.35 (d, 1H); 7.73 (d, 2H); 7.63 (s,1H); 7.61 (d, 1H); 7.55 (d, 2H); 7.41 (d, 1H); 7.33 (d, 1H); 7.33 (d,1H); 6.60 (d, 1H); 4.66 (s, 2H).

Step C: Preparation of 3-(N-Benzoyl-5-indolyl)methyl-2-butyl-6-methylquinazolin-4(3H)-one

To a solution of 2-butyl-6-methyl-quinazolin-4-(1H)-one, Example 1, (1eq) in DMF was added 1.1 eq of 60% NaH. After 5 minutes the evolution ofhydrogen had ceased and 1.3 eq of Step B was added. The mixture wasstirred for 2.5 hours and the DMF removed in vacuo. The resultant brownoil was flash chromatographed to yield the titled compound.

EXAMPLE 21 Preparation of2-Butyl-3-[N-(2-carboxybenzoyl)-5-indolyl]-methyl-6-methylquinazolin-4(3H)-one

Step A: Preparation of2-Butyl-3-(5-indolyl)methyl-6-methylquinzolin-4(3H)-one

To a suspension of the product of Example 20 in methanol was addedexcess 2N NaOH and the mixture heated to 60° C. After 18 hours themethanol was removed in vacuo. The reaction mixture was diluted with H₂O and extracted with CH₂ Cl₂. The combined extracts were dried over Na₂SO₄, filtered and concentrated to yield the titled compound.

Step B: Preparation of2-Butyl-3-[N-(2-carboxybenzoyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

To a solution of 1 eq of the product of Step A in DMF was added 1.1 eqof 60% NaH, followed by 1.2 eq of phthalic anhydride. This mixture wasstirred for 16 hours and the DMF removed in vacuo. The resultant oil wasflash column chromatographed to yield the titled compound.

EXAMPLE 222-Butyl-3-[N-(2-carboxy-3-nitrobenzoyl)-5-indolyl]-methyl-6-methyl-quinazolin-4(3H)-one

Following the procedure of Example 21, Step B and replacing phthalicanhydride with 3-nitrophthalic anhydride the titled compound can beprepared.

EXAMPLE 23Butyl-3-[N-(2-carboxy-3,6-dichlorobenzoyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 21, Step B and replacing phthalicanhydride with 3,6-dichlorophthalic anhydride the titled compound can beprepared.

EXAMPLE 243-[N-(2-carboxy-4,5-dichlorobenzoyl)-5-indolyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5b]pyridine

Following the procedure of Example 21, Step B and replacing phthalicanhydride with 4,5-dichlorophthalic anhydride the titled compound can beprepared.

EXAMPLE 252-Butyl-3-[N-(2-carbamylbenzoyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

To a solution of 1 eq of the product of Example 21, Step A in DMF wasadded 2 eq of NaH and the mixture stirred for a few minutes. 1.5 eq ofisatoic anhydride was added to the reaction mixture and it was stirredfor 16 hours. The solvent was removed in vacuo and the resultant residueis flash column chromatographed.

EXAMPLE 263-[N-(2-methylcarbamoylbenzoyl)-5-indolyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine

To a solution of the product of Example 25 in CH₂ Cl₂ at 0° C. was added0.2 mL of 10% trimethylinsilyldiazomethane. After stirring for 10minutes, 0.2 mL of acetic acid was added. The volatiles are removed invacuo. The product can be isolated using preparative TLC.

EXAMPLE 272-Butyl-3-[N-(2-cyanobenzoyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Step A: Preparation of 2-Cyanobenzoyl Chloride

A mixture of 2-cyanobenzoic acid (2 g, 13.6 mmol) and 15 ml of thionylchloride was refluxed overnight. Excess thionyl chloride was removed invacuo and the resultant 2-cyanobenzoyl chloride obtained as such as anoff white solid was used in the above acylation.

Step B: Preparation of2-Butyl-3-[N-(2-cyanobenzoyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-on

To a solution of 1.0 eq the product of Example 21, Step A in DMF isadded 1.2 eq of 60% NaH. After stirring for 5 minutes, 2-cyanobenzoylchloride (1.5 eq) is added to the reaction mixture. The resultantsolution is stirred for 16 hours and the DMF removed in vacuo. Theresultant oil can be flash chromatographed to yield the titled compound.

EXAMPLE 282-Butyl-3-[N-(2-tetrazol-5-yl-benzoyl)-5-indolyl]-methyl-6-methylquinazolin-4(3H)-one

To a solution of 1.0 eq of the product of Example 27, Step B in tolueneis added 1.2 eq of trimethyltin azide. The mixture is heated at refluxfor 18 hours. Toluene was removed in vacuo and the resultant oil isdissolved in THF and treated with 2.5N HCl at 0° C. for 5 minutes. Thevolatiles were removed in vacuo and the resultant oil can be flashchromatographed to yield the titled compound.

EXAMPLE 292-Butyl-3-[N-(2-cyanobenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

To a solution of 1.0 eq of the product of Example 21, Step A in DMF isadded 1.1 eq of 60% NaH followed by 1.2 eq of α-bromo-o-tolunitrile. Themixture was stirred for 16 hours and then concentrated in vacuo. Theresultant oil is flash chromatographed to yield the titled compound.

EXAMPLE 302-Butyl-3-[N-(2-tetrazol-5-yl-benzyl)-5-indolyl]-methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 28, but utilizing the product ofExample 29, the titled compound can be prepared.

EXAMPLE 312-Butyl-3-(N-(2-cyano-6-chlorobenzyl)-5-indolyl]-6-methylquinazolin-4(3H)-one

Step A: Preparation of 2-chloro-6-cyanobenzyl bromide

To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g,13.2mmol) in 20 mL of CCl₄ was added 2.6 g (14.4 mmol, 1.1 eq) ofN-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3hours and then cooled, diluted with 500 mL of CH₂ Cl₂ and washed with200 mL of H₂ O and 200 mL of brine. The organic phase was dried overMgSO₄, filtered and concentrated in vacuo. The resultant oil was flashchromatographed with 5:1 hexane/ethyl acetate to yield the titledcompound (1.4 g, 46%) as a yellow oil.

FAB-MS: m/e=230 (M+1)

¹ H NMR (400 MHz, CDCl₃, ppm) d 7.63 (dd, 1H); 7.58 (dd, 1H); 7.37 (t,1H); 4.74 (s, 2H).

Step B: Preparation of2-Butyl-3-[N-(2-cyano-6-chlorobenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 29 but replacingα-bromo-o-tolunitrile with the product of Step A the titled compound canbe prepared.

EXAMPLE 322-Butyl-3-[N-(2-tetrazol-5-yl-6-chlorobenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 28 but utilizing the product ofExample 12 the titled compound can be prepared.

EXAMPLE 332-Butyl-3-[N-(2-carbomethoxybenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Step A Preparation of Methyl-2-bromomethylbenzoate

To a solution of 2.3 g (15.3 mmol) of methyl o-methylbenzoate (methylo-toluate) in 20 mL of refluxing CCl₄ was added 3 g ofN-bromosuccinimide and 0.10 g AIBN. After 2.5 hours the mixture wascooled, diluted with 500 mL of CH₂ Cl₂ and washed with 200 mL of H₂ Oand 200 mL Of brine. The organic phase was dried over MgSO₄, filteredand concentrated in vacuo. The resultant oil was flash chromatographedwith 5:1 hexane/ethyl acetate to yield the titled compound (2.56 g,73%).

FAB-MS: m/e=230 (M+1)

¹ H NMR (300 MHz, CDCl₃, ppm) d 7.97 (d, 1H); 7.51 (d, 1H); 7.48 (d,1H); 7.39 (dd, 1H); 4.96 (s, 2H); 3.93 (s, 3H).

Step B: Preparation of2-Butyl-3-[N-(2-carbomethoxybenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)one

Following the procedure of Example 29 but replacingα-bromo-o-tolunitrile with the product of Step A the titled compound canbe prepared.

EXAMPLE 342-Butyl-3-[N-(2-carboxybenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

To a solution of the product of Example 33, Step B in methanol is added1N NaOH. The mixture is stirred for 16 hours. The volatiles are removedin vacuo and the water removed azeotropically with toluene. The clearoil can be flash chromatographed to yield the titled compound.

EXAMPLE 352-Butyl-3-[N-(2-carbomethoxy-4,5-dichlorobenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Step A: Preparation of 2-carbomethoxy 4,5-dichlorobenzoic acid

To a solution of 4,5-dichlorophthalic anhydride (1.0 g, 4.61 mmol) in 15mL of methanol was added 0.25 g (9.22 mmol, 2.0 eq) of sodium methoxide.The suspension was stirred for 3 days and the methanol was removed invacuo. The resultant white solid was suspended in 500 mL of CH₂ Cl₂ andwashed with 1N HCl. The organic phase was dried over anhydrous Na₂ SO₄,filtered and the volatiles removed in vacuo to yield 1.06 g (92.5%) ofthe titled compound as a white powder.

FAB-MS: m/e=249 (M+1)

¹ H NMR (300 MHz, CD₃ OD, ppm) d 8.26 (s, 1H); 8.11 (s, 1H): 4.10 (s,3H).

Step B: Preparation of Methyl-4,5-dichloro-2-(hydroxymethyl)benzoate

To a solution of the product of Step A (1.06 g, 4.28 mmol) in 5 mL ofTHF at 0° C. was added borane-methyl sulfide (6.42 mL of 2M solution inTHF, 12.84 mmol, 3.0 eq). The reaction was allowed to warm to roomtemperature. After 16 hours the reaction was cooled to 0° C. andquenched with methanol. The volatiles were removed in vacuo and the oilflash chromatographed with 2:1 hexane/ethyl acetate to yield the titledcompound (169 mg, 17%). Approximately 80% of the starting material wasalso recovered.

FAB-MS: m/e=235 (M+1)

¹ H NMR (300 MHz, CDCl₃, ppm) d 8.08 (s, 1H); 7.62 (s, 1H); 4.79 (d,2H); 3.94 (s, 3H); 3.54 (t, 1H).

Step C: Preparation of Methyl 2-(bromomethyl)-4,5 dichlorobenzoate

To a solution of 169 mg (0.72 mmol) of the product of Step B in 3 mL ofCH₂ Cl₂ at 0° C. was added 283 mg (1.08 mmol, 1.5 eq) oftriphenylphosphine and 360 mg (1.08 mmol, 1.5 eq) of carbontetrabromide. The mixture was stirred for 16 hours and quenched withmethanol. The reaction was concentrated in vacuo and the resultant oilwas flash chromatographed with 2:1 hexane/ethyl acetate to afford thetitled compound (107 mg, 50%) as a brownish orange oil.

FAB-MS: m/e=297 (M+1)

¹ H NMR (300 MHz, CDCl₃, ppm) d 8.06 (s, 1H); 7.58 (s, 1H); 4.86 (s,2H); 3.94 (s, 3H).

Step D: Preparation of3-[N-(2-carbomethoxy-4,5-dichlorobenzyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 29 but replacingα-bromo-o-tolunitrile with the product of Step C the titled compound canbe prepared.

EXAMPLE 362-Butyl-3-[N-(2-cyanobenzoyl)-5-dihydroindolyl]methyl-6-methylquinazolin-4(3H)-one

Step A: Preparation of3-(5-dihydroindolyl)methyl-6-methylquinazolin-4(3H)-one

To a solution of 1.0 eq of the product of Example 21, Step A in aceticacid is slowly added 1.1 eq of NaCNBH₃. After 45 minutes the reaction isdiluted with H₂ O and neutralized carefully with aqueous solution ofsaturated NaHCO₃. The pH is adjusted to 9 with the addition of solidNaOH and then extracted 3 times with CH₂ Cl₂. The combined extracts aredried over Na₂ SO₄, filtered and concentrated in vacuo. Flash columnchromatography of the crude material provides the titled compound.

Step B: Preparation of3-[N-(2-cyanobenzoyl)-5-dihydroindolyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine

To a solution 1.0 eq of the product of Step A in CH₂ Cl₂ is added 0.05eq of 4-dimethylaminopyridine and 1.1 eq of 2-cyanobenzoyl chloride. Thereaction is stirred for 1 hour and then diluted with CH₂ Cl₂ and washedwith aqueous saturated NaHCO₃ solution and brine. The organic phase isdried over MgSO₄, filtered and concentrated in vacuo. The resultant oilcan be flash chromatographed to yield the titled compound.

EXAMPLE 372-Butyl-3-[N-(2-tetrazol-5-yl-benzoyl)-5-dihydroindol-yl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 28 but utilizing the product ofExample 36 the titled compound can be prepared.

EXAMPLE 382-Butyl-3-[N-(2-acetoxybenzoyl)-5-dihydroindolyl]-methyl-6-methylquinazolin-4(3H)one

To a solution of 1.0 eq of the product of Example 36, Step A and 1.1 eqof o-salicyloyl chloride in CH₂ Cl₂ is added aqueous solution ofsaturated NaHCO₃. The biphasic mixture is stirred for 16 hours and thendiluted with CH₂ Cl₂, washed with aqueous solution of saturated NaHCO₃and brine. The organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. The resultant oil is flash chromatographed withethyl acetate to yield the titled compound.

EXAMPLE 39 2-Butyl-3-[N(2-acetoxybenzoyl)-5-indolyl]methyl-6-methylquinazolin-4(3H)-one

To a refluxing solution of 1.0 eq of the product of Example 38 in1,4-dioxane was added 3.0 eq of 2,3-dichloro-5,6-dicyano-1,4-quinone.The mixture is refluxed for 6 hours then cooled and concentrated invacuo. The resultant oil is flash chromatographed to yield the titledcompound.

EXAMPLE 402-Butyl-3-[N-(2-carboxybenzoyl)-5-dihydroindolyl]-methyl-6-methylquinazolin-4(3H)-one

To a solution of 1.0 eq of the product of Example 36, Step A in CH₂ Cl₂is added 0.05 eq of 4-dimethylaminopyridine and 1.1 eq of phthalicanhydride. The reaction is stirred for 2 hours and then concentrated invacuo. The resultant oil is flash chromatographed to yield the titledcompound.

EXAMPLE 412-Butyl-3-[N-(2-carboxy-3,6-dichlorobenzoyl)-5-dihydroindolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 40, but replacing phthalic anhydridewith 3,6-dichlorophthalic anhydride the titled compound can be prepared.

EXAMPLE 422-Butyl-3-[N-(2-carboxy-4,5-dichlorobenzoyl)-5-dihydroindolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 40, but replacing phthalic anhydridewith 4,5-dichlorophthalic anhydride the titled compound can be prepared.

EXAMPLE 432-Butyl-3-[N-(1-carbomethoxy-1-phenyl)methyl-5-dihydroindolyl]methyl-6-methylquinazolin-4(3H)-one

To a solution of 1.0 eq of the product of Example 36, Step A in DMF isadded NaH 2 eq and the mixture is stirred for 15 min. Methylα-bromophenylacetate 2.2 equiv is added to the reaction mixture andstirred for 24 h. The DMF is removed in vacuo and residue is flashchromatographed to afford the titled compound.

EXAMPLE 442-Butyl-3-[N-(1-carboxy-1-phenyl)methyl-5-dihydroindolyl]-methyl-6-methylquinazolin-4(3H)-one

Methyl ester, the product of Example 43, is treated with 1N NaOH inmethanol for 24 h. The volatiles are removed in vacuo and the residue isflash chromatographed to give the titled acid.

EXAMPLE 452-Butyl-3-[N-(1-cyano-1-phenyl)methyl-5-dihydroindolyl]methyl-6-methylquinazolin-4(3H)-one

A mixture of 1.0 eq of the product of Example 36, Step A, 7.4 eq ofbenzaldehyde, and 7.4 equiv of KCN in AcOH and methanol is stirred forfive days. The volatiles are removed in vacuo and the residue is flashchromatographed to afford the titled compound.

EXAMPLE 462-Butyl-3-[N-(1-cyano-1-o-tolyl)methyl-5-dihydroindolyl]-methyl-6-methylquinazolin-4(3H)-one

The titled compound can be prepared from the product of Example 36, StepA o-tolualdehyde, KCN and AcOH according to the procedure of Example 45.

EXAMPLE 472-Butyl-3-[N-(1-cyano-1-m-tolyl)methyl-5-dihydroindolyl]-methyl-6-methylquinazolin-4(3H)-one

The titled compound can be prepared from the Product of Example 36, StepA m-tolualdehyde, KCN and AcOH according to the procedure of Example 45.

EXAMPLE 482-Butyl-3-[N-(1-cyano-1-p-tolyl)methyl-5-dihydroindolyl]-methyl-6-methylquinazolin-4(3H)-one

The titled compound can be prepared from the product of Example 36, StepA p-tolualdehyde, KCN, and AcOH in methanol according to the procedureof Example 45.

EXAMPLE 492-Butyl-3-[N-(1-tetrazol-5-yl-1-phenyl)methyl-5-dihydroindolyl]methyl-6-methylquinazolin-4(3H)-one

Following the procedure of Example 28, but utilizing the product ofExample 45, the titled compound can be prepared.

The compounds shown in Tables I-III can be prepared utilizing theprocedures outlined above.

    __________________________________________________________________________     ##STR50##                                                                    R.sup.1                                                                            a     X         R.sup.a                                                                         R.sup.b                                                                         R.sup.c                                                                          R.sup.d                                                                          Z       R.sup.8a                               __________________________________________________________________________    n-butyl                                                                            single bond                                                                         O         H H H  H  CO.sub.2 H                                                                            H                                      n-propyl                                                                           single bond                                                                         O         H H H  NO.sub.2                                                                         CO.sub.2 H                                                                            Me                                     n-butyl                                                                            single bond                                                                         O         Cl                                                                              H H  Cl CO.sub.2 H                                                                            N(Me)(CO.sub.2 Me)                     n-butyl                                                                            single bond                                                                         O         H Cl                                                                              Cl H  CO.sub.2 H                                                                            Me                                     n-butyl                                                                            single bond                                                                         O         H H H  H  NHCO.sub.2 H                                                                          N(Me)(CO.sub.2 Me)                     n-butyl                                                                            single bond                                                                         O         H H H  H  NHCO.sub.2 CH.sub.3                                                                   N(Me)(CO.sub.2 Me)                     n-butyl                                                                            single bond                                                                         O         H H H  H  CN      N(Me)(CO.sub.2 Me)                     n-butyl                                                                            single bond                                                                         O         H H H  H  1H-tetrazol-5-yl                                                                      N(Me)(CO.sub.2 Me)                     n-butyl                                                                            single bond                                                                         H, H      H H H  H  CN      N(Me)(CO.sub.2 iBu)                    n-butyl                                                                            single bond                                                                         H, H      H H H  H  1H-tetrazol-5-yl                                                                      N(Me)(CO.sub.2 iBu)                    n-propyl                                                                           single bond                                                                         H, H      Cl                                                                              H H  H  CN      N(Bz)(CO.sub.2 iBu)                    n-butyl                                                                            single bond                                                                         H, H      Cl                                                                              H H  H  1H-tetrazol-5-yl                                                                      N(Bz)(CO.sub.2 iBu)                    n-butyl                                                                            single bond                                                                         H, H      H H H  H  CO.sub.2 CH.sub.3                                                                     N(Bz)(CO.sub.2 Bu)                     n-butyl                                                                            single bond                                                                         H, H      H H H  H  CO.sub.2 H                                                                            H                                      n-butyl                                                                            single bond                                                                         H, H      H Cl                                                                              Cl H  CO.sub.2 CH.sub.3                                                                     N(Boz)(Pn)                             n-propyl                                                                           single bond                                                                         H, H      H Cl                                                                              Cl H  CO.sub.2 H                                                                            CH.sub.3                               n-butyl                                                                            absent                                                                              O         H H H  H  CN      N(Boz)(Bz)                             n-butyl                                                                            absent                                                                              O         H H H  H  1H-tetrazol-5-yl                                                                      N(Boz)(Bz)                             n-butyl                                                                            absent                                                                              O         H H H  H  OC(O)CH.sub.3                                                                         N(Me)(CO.sub.2 Me)                     n-butyl                                                                            single bond                                                                         O         H H H  H  OC(O)CH.sub.3                                                                         N(Bz)(CO.sub.2 Pn)                     n-propyl                                                                           absent                                                                              O         H H H  H  CO.sub.2 H                                                                            N(Me)(CO.sub.2 iBu)                    n-butyl                                                                            absent                                                                              O         Cl                                                                              H H  Cl CO.sub.2 H                                                                            N(Me)(CO.sub.2 Me)                     n-butyl                                                                            absent                                                                              O         H Cl                                                                              Cl H  CO.sub.2 H                                                                            N(Me)(CO.sub.2 Pn)                     n-butyl                                                                            absent                                                                              H, CO.sub.2 CH.sub.3                                                                    H H H  H  H       N(Boz)(Pn)                             n-butal                                                                            absent                                                                              H, CO.sub.2 H                                                                           H H H  H  H       N(Boz)(Pn)                             n-propyl                                                                           absent                                                                              H, CN     H H H  H  H       N(Bz)[CON(Me)(Et)]                     n-butyl                                                                            absent                                                                              H, CN     H H H  H  CH.sub.3                                                                              N(Bz)(CO.sub.2 Me)                     n-butyl                                                                            absent                                                                              H, CN     H H H  CH.sub.3                                                                         H       N(Me)(CO.sub.2 Me)                     n-butyl                                                                            absent                                                                              H, CN     H H CH.sub.3                                                                         H  H       N(Boz)(Pn)                             n-butyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H H  H  H       N(Bz)[CON(Me)(Et)]                     n-propyl                                                                           absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H H  H  CH.sub.3                                                                              N(Bz)(CO.sub.2 Me)                     n-butyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H H  CH.sub.3                                                                         H       N(Me)(CO.sub.2 Me)                     n-butyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H CH.sub.3                                                                         H  H       N(Boz)(Pn)                             __________________________________________________________________________     ##STR51##                                                                    R.sup.1                                                                            a     X         R.sup.a                                                                         R.sup.b                                                                         R.sup.c                                                                          R.sup.d                                                                          Z       R.sup.17                                                                            R.sup.18                         __________________________________________________________________________    n-butyl                                                                            single bond                                                                         O         H H H  H  CO.sub.2 H                                                                            CH.sub.3                                                                            H                                n-butyl                                                                            single bond                                                                         O         H H H  NO.sub.2                                                                         CO.sub.2 H                                                                            CH.sub.3                                                                            H                                n-butyl                                                                            single bond                                                                         O         Cl                                                                              H H  Cl CO.sub.2 H                                                                            2-ClPh                                                                              H                                n-butyl                                                                            single bond                                                                         O         H Cl                                                                              Cl H  CO.sub.2 H                                                                            CH.sub.3                                                                            CH.sub.3                         n-propyl                                                                           single bond                                                                         O         H H H  H  NHCO.sub.2 H                                                                          2-CH.sub.3Ph                                                                        CH.sub.3                         n-butyl                                                                            single bond                                                                         O         H H H  H  NHCO.sub.2 CH.sub.3                                                                   2-CF.sub.3Ph                                                                        CH.sub.3                         n-butyl                                                                            single bond                                                                         O         H H H  H  CN      2-ClPh                                                                              CH.sub.3                         n-butyl                                                                            single bond                                                                         O         H H H  H  1H-tetrazol-5-yl                                                                      2-ClPh                                                                              CH.sub.3                         n-butyl                                                                            single bond                                                                         H, H      H H H  H  CN      2-CH.sub.3Ph                                                                        CH.sub.3                         n-propyl                                                                           single bond                                                                         H, H      H H H  H  1H-tetrazol-5-yl                                                                      2-CH.sub.3Ph                                                                        CH.sub.3                         n-butyl                                                                            single bond                                                                         H, H      Cl                                                                              H H  H  CN      2-CF.sub. 3Ph                                                                       CH.sub.3                         n-butyl                                                                            single bond                                                                         H, H      Cl                                                                              H H  H  1H-tetrazol-5-yl                                                                      2-CF.sub.3Ph                                                                        CH.sub.3                         n-butyl                                                                            single bnd                                                                          H, H      H H H  H  CO.sub.2 CH.sub.3                                                                     2-ClPh                                                                              CH.sub.3                         n-butyl                                                                            single bond                                                                         H, H      H H H  H  CO.sub.2 H                                                                            2-ClPh                                                                              CH.sub.3                         n-propyl                                                                           single bond                                                                         H, H      H Cl                                                                              Cl H  CO.sub.2 CH.sub.3                                                                     2-CH.sub.3Ph                                                                        CH.sub.3                         n-butyl                                                                            single bond                                                                         H, H      H Cl                                                                              Cl H  CO.sub.2 H                                                                            2-CH.sub.3Ph                                                                        CH.sub.3                         n-butyl                                                                            absent                                                                              O         H H H  H  CN      CH.sub.3                                                                            CH.sub.3                         n-butyl                                                                            absent                                                                              O         H H H  H  1H-tetrazol-5-yl                                                                      CH.sub.3                                                                            CH.sub.3                         n-butyl                                                                            absent                                                                              O         H H H  H  OC(O)CH.sub.3                                                                         CH.sub.3                                                                            Cl                               n-propyl                                                                           single bond                                                                         OH        H H H  H  OC(O)CH.sub.3                                                                         CH.sub.3                                                                            Cl                               n-butyl                                                                            absent                                                                              O         H H H  H  CO.sub.2 H                                                                            CH.sub.3                                                                            CO.sub.2 H                       n-butyl                                                                            absent                                                                              O         Cl                                                                              H H  Cl CO.sub.2 H                                                                            CH.sub.3                                                                            2-ClPh                           n-butyl                                                                            absent                                                                              O         H Cl                                                                              Cl H  CO.sub.2 H                                                                            CH.sub.3                                                                            2-CH.sub.3Ph                     n-butyl                                                                            absent                                                                              H, CO.sub.2 CH.sub.3                                                                    H H H  H  H       CH.sub.3                                                                            2-CF.sub.3Ph                     n-propyl                                                                           absent                                                                              H, CO.sub.2 H                                                                           H H H  H  H       CH.sub.3                                                                            CH.sub.2Ph                       n-butyl                                                                            absent                                                                              H, CN     H H H  H  H       CH.sub.3                                                                            2-ClPh                           n-butyl                                                                            absent                                                                              H, CN     H H H  H  CH.sub.3                                                                              CH.sub.3                                                                            2-CH.sub.3Ph                     n-butyl                                                                            absent                                                                              H, CN     H H H  CH.sub.3                                                                         H       CH.sub.3                                                                            2-CF.sub.3Ph                     n-butyl                                                                            absent                                                                              H, CN     H H CH.sub.3                                                                         H  H       CH.sub.3                                                                            CH.sub.2Ph                       n-propyl                                                                           absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H H  H  H       CH.sub.3                                                                            2-ClPh                           n-butyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H H  H  CH.sub.3                                                                              CH.sub.3                                                                            2-CH.sub.3Ph                     n-butyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H H  CH.sub.3                                                                         H       CH.sub.3                                                                            2-CF.sub.3 Ph                    n-butyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H H CH.sub.3                                                                         H  H       CH.sub.3                                                                            CH.sub.2Ph                       __________________________________________________________________________     ##STR52##                                                                    R.sup.1                                                                             a     X         R.sup.a                                                                          R.sup.b                                                                          R.sup.c                                                                          R.sup.d                                                                           Z       R.sup.16                           __________________________________________________________________________    n-propyl                                                                            single bond                                                                         O         H  H  H  H   CO.sub.2 H                                                                            CH.sub.2 Ph                        n-butyl                                                                             single bond                                                                         O         H  H  H  NO.sub.2                                                                          CO.sub.2 H                                                                            CH.sub.2 Ph                        n-butyl                                                                             single bond                                                                         O         Cl H  H  Cl  CO.sub.2 H                                                                            2-CO.sub.2 HPh                     n-butyl                                                                             single bond                                                                         O         H  Cl Cl H   CO.sub.2 H                                                                            2-ClPh                             n-butyl                                                                             single bond                                                                         O         H  H  H  H   NHCO.sub.2 H                                                                          CH.sub.2 OH                        n-propyl                                                                            single bond                                                                         O         H  H  H  H   NHCO.sub.2 CH.sub.3                                                                   CO.sub.2 CH.sub.2                  n-butyl                                                                             single bond                                                                         O         H  H  H  H   CN      2-ClPh                             n-butyl                                                                             single bond                                                                         O         H  H  H  H   1H-tetrazol-5-yl                                                                      2-ClPh                             n-butyl                                                                             single bond                                                                         H, H      H  H  H  H   CN      2-CH.sub.3Ph                       n-butyl                                                                             single bond                                                                         H, H      H  H  H  H   1H-tetrazol-5-yl                                                                      2-CH.sub.3Ph                       n-propyl                                                                            single bond                                                                         H, H      Cl H  H  H   CN      CH.sub.2 Ph                        n-butyl                                                                             single bond                                                                         H, H      Cl H  H  H   1H-tetrazol-5-yl                                                                      CH.sub.2 Ph                        n-butyl                                                                             single bond                                                                         H, H      H  H  H  H   CO.sub.2 CH.sub.3                                                                     CO.sub.2 CH.sub.3                  n-butyl                                                                             single bond                                                                         H, H      H  H  H  H   CO.sub.2 H                                                                            CO.sub.2 H                         n-butyl                                                                             single bond                                                                         H, H      H  Cl Cl H   CO.sub.2 CH.sub.3                                                                     CO.sub.2 CH.sub.3                  n-propyl                                                                            single bond                                                                         H, H      H  Cl Cl H   CO.sub.2 H                                                                            CH.sub.2 CH.sub.3                  n-butyl                                                                             absent                                                                              O         H  H  H  H   CN      CH.sub.2 OH                        n-butyl                                                                             absent                                                                              O         H  H  H  H   1H-tetrazol-5-yl                                                                      CH.sub.2 OH                        n-butyl                                                                             absent                                                                              O         H  H  H  H   OC(O)CH.sub.3                                                                         CH.sub.2Ph                         n-butyl                                                                             single bond                                                                         O         H  H  H  H   OC(O)CH.sub.3                                                                         CH.sub.2Ph                         n-propyl                                                                            absent                                                                              O         H  H  H  H   CO.sub.2 H                                                                            2-CF.sub.3Ph                       n-butyl                                                                             absent                                                                              O         Cl H  H  Cl  CO.sub.2 H                                                                            2-CF.sub.3Ph                       n-butyl                                                                             absent                                                                              O         H  Cl Cl H   CO.sub.2 H                                 n-butyl                                                                             absent                                                                              H, CO.sub.2 CH.sub.3                                                                    H  H  H  H   H       CH.sub.2 Ph                        n-butyl                                                                             absent                                                                              H, CO.sub.2 H                                                                           H  H  H  H   H       CH.sub.2 Ph                        n-propyl                                                                            absent                                                                              H, CN     H  H  H  H   H       2-ClPh                             n-butyl                                                                             absent                                                                              H, CN     H  H  H  H   CH.sub.3                                                                              2-CH.sub.3Ph                       n-butyl                                                                             absent                                                                              H, CN     H  H  H  CH.sub.3                                                                          H       2-CF.sub.3Ph                       n-butyl                                                                             absent                                                                              H, CN     H  H  CH.sub.3                                                                         H   H       2-ClPh                             n-butyl                                                                             absent                                                                              H, 1H-tetrazol-5-yl                                                                     H  H  H  H   H       2-ClPh                             n-propyl                                                                            absent                                                                              H, 1H-tetrazol-5-yl                                                                     H  H  H  H   CH.sub.3                                                                              2-CH.sub.3Ph                       n-butyl                                                                             absent                                                                              H, 1H-tetrazol-5-yl                                                                     H  H  H  CH.sub.3                                                                          H       2-CF.sub.3Ph                       n-butyl                                                                             absent                                                                              H, 1H-tetrazol-5-yl                                                                     H  H  CH.sub.3                                                                         H   H       2-ClPh                             __________________________________________________________________________

What is claimed is:
 1. A compound of structural formula I or apharmaceutically acceptable salt ##STR53## wherein the heterocycle isdefined as: ##STR54## R¹ is: (a) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂-C₆)-alkynyl each of which is unsubstituted or substituted with asubstituent selected from the group consisting of:i) aryl as definedbelow, ii) (C₃ -C₇)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH₂, vi)NH(C₁ -C₄)-alkyl, vii) N[(C₁ -C₄)-alkyl]₂, viii) NHSO₂ R², ix) CF₃, x)COOR², or xi) SO₂ NHR^(2a) ; (b) aryl, wherein aryl is defined as phenylor naphthyl, unsubstituted or substituted with 1 or 2 substituentsselected from the group consisting of:i) Br, I, Cl, F, ii) (C₁-C₄)-alkyl, iii) (C₁ -C₄)-alkoxy, iv) NO₂ v) CF₃ vi) SO₂ NR^(2a) R^(2a),vii) (C₁ -C₄)-alkylthio, viii) hydroxy, ix) amino, x) (C₃-C₇)-cycloalkyl, or xi) (C₃ -C₁₀)-alkenyl; (c) heteroaryl, whereinheteroaryl is selected from the group consisting of pyridyl, thienyl,furyl, imidazolyl and thiazolyl or 6-membered heteroaromatic moiety,which can contain one or two members selected from the group consistingof N, O, S and wherein the heteroaryl is unsubstituted, monosubstitutedor disubstituted with substituents selected from the group consistingof:i) Cl, Br, I, or F, ii) OH, iii) SH, iv) NO₂, v) (C₁ -C₄)-alkyl, vi)(C₂ -C₄)-alkenyl, vii) (C₂ -C₄)-alkynyl, viii) (C₁ -C₄)-alkoxy, or ix)CF₃, or (d) (C₁ -C₄)-perfluoroalkyl; E is:(a) a single bond, (b)--S(O)_(n) (CH₂)_(s) --, or (c) --O--; n is 0 to 2; s is 0 to 5; J¹ is(a)--C(═M)--, (b) J¹ and L are connected together to form a 6-carbonaromatic ring substituted with R^(7a), R^(7b), R^(8a) and R^(8b) or (c)J¹ and L are connected together to form a 6-membered aromatic ringcontaining one nitrogen atom not at J¹, substituted with R^(7a), R^(7b),R^(8a) and R^(8b) ; K¹ is (a)--C(═M)--, (b) K¹ and L are connectedtogether to form a 6-carbon aromatic ring substituted with R^(7a),R^(7b), R^(8a) and R^(8b), or (c) K¹ and L are connected together toform a 6-membered aromatic ring containing one nitrogen atom,substituted on the carbon atoms with R^(7a), R^(7b) and R^(8b) ;provided that one and only one of J¹ and K¹ is --C(═M)--; one of a¹ orb¹ is a double bond in structures Ia provided that when J¹ is --C(═M)--then b¹ is a double bond and when K¹ is --C(═M)-- then a¹ is a doublebond; L is the point of attachment of the 6-membered fused aromatic ringoptionally containing one nitrogen atom; M is O, S or NR¹⁵ ; R² is:(a)H, or (b) (C₁ -C₆)-alkyl; R^(2a) is:(a) R², (b) CH₂ -aryl, or (c) aryl;R^(7a) and R^(7b) are independently(a) H, (b) (C₁ -C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂ -C₆)-alkynyl, (c) Cl, Br, I, F, (d) CF₃, or (e) whenR^(7a) and R^(7b) are bonded to adjacent carbon atoms, they can bejoined to form a phenyl ring; R^(8a) and R^(8b) are independently(a) H,(b) aryl-(C₁ -C₄)-alkyl, (c) heteroaryl-(C₁ -C₄)-alkyl, (d) (C₁-C₆)-alkyl, which is unsubstituted or substituted with a substituentselected from the group consisting of: --CON(R^(2a))₂, --heteroaryl,--S(O)_(x) --R²¹, --tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂ NH-heteroaryl,--SO₂ NHCOR²¹, --PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN, --NR² COOR²¹,--OH, --NH₂, guanidino, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁-C₄)-alkyl-amino, (C₁ -C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a),--O--COR^(2a), or aryl, (e) --CO-aryl, (f) (C₃ -C₇)-cycloalkyl, (g) Cl,Br, I, F, (h) --OH, (i) --OR²¹, (j) --SH, (k) --S(O)_(n) --(C₁-C₄)-alkyl, (l) --COR^(2a), (m) --CO₂ H, (n) --CO₂ --(C₁ -C₄)-alkyl, (o)--SO₃ H, (p) --NR² R²¹, (q) --NR² COR²¹, (r) --NR² COOR²¹, (s) --SO₂NHR^(2a), (t) --SO₂ NR² R^(2a), (u) --NO₂, (v) --NHSO₂ CF₃, (w)--CONR^(2a) R^(2a), (x) --(C₁ -C₄)-perfluoroalkyl, (y) --COOR², (z)--SO₃ H, (aa) --N(R²)SO₂ R²¹, (bb) --NR² CONR⁴ R²¹, (cc) --OC(═O)NR²¹R^(2a), (dd) --aryl, (ee) --NHSO₂ CF₃, (ff) --SO₂ NH-heteroaryl, (gg)--SO₂ NHCOR²¹, (hh) --CONHSO₂ R²¹, (ii) --PO(OR²)₂, (jj)--tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll) --SO₂ NHCN, or (mm)--heteroaryl; X is:(a) O, (b) H; H, (c) H; CO₂ --(C₁ -C₄)-alkyl, (d) H;CO₂ H, (e) H; CN, (f) H; tetrazolyl, or (g) H; CONHSO₂ R¹⁴, R⁹ and R¹⁰are each independently:(a) H, (b) Cl, Br, I, F, (c) NO₂, (d) (C₁ -C₆-alkyl, (e) (C₁ -C₆)-acyloxy, (f) (C₃ -C₆)-cycloalkyl, (g) (C₁-C₆)-alkoxy, (h) --NHSO₂ R^(2a), (i) hydroxy-(C₁ -C₄)-alkyl, (j) (C₁-C₄)-alkyl-aryl, (k) S(O)_(n) --(C₁ -C₄)-alkyl, (n) NR^(2a) R^(2a), (q)CF₃, (r) --SO₂ NHR^(2a), (s) furyl, (t) aryl, wherein aryl is phenyl ornaphthyl, unsubstituted or substituted with one or two substituentsselected from the group consisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxy, NO₂, CF₃, (C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁-C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --CO₂ H, or --CO₂ --(C₁ -C₄)-alkyl,or (u) when R⁹ and R¹⁰ are bonded to adjacent carbon atoms, they can bejoined to form an aryl ring; R¹¹ and R¹² are independently:(a) H, (b)Cl, Br, I, F, (c) NO₂, (d) NH₂, (e) NH[(C₁ -C₄)-alkyl], (f) N](C₁-C₄)-alkyl]₂, (g) SO₂ NHR^(2a), (h) CF₃, (i) (C₁ -C₄)-alkyl, (j) (C₁-C₄)-alkoxy, or (k) when R¹¹ and R¹² are bonded to adjacent carbonatoms, they can be joined to form an aryl ring; Z is:(a) --H, (b) --CO₂R^(2a), (c) --SO₃ R¹³, (d) --NHSO₂ CF₃, (e) --PO(OR¹³)₂, (f) --SO₂NHR¹⁴, (g) --CONHOR¹³, ##STR55## (i) --CN, (j) --SO₂ NH-heteroaryl,wherein heteroaryl is an unsubstituted, monosubstituted or disubstitutedfive or six membered aromatic ring Selected from the group consisting ofpyridine, thienyl, furyl, imidazolyl and thiazolyl and wherein thesubstituents are members selected from the group consisting of: --OH,--SH, --(C₁ -C₄)-alkyl, --(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂,--CO₂ H, --CO₂ --(C₁ -C₄)-alkyl, --NH₂, NH[(C₁ -C₄)-alkyl] and --N[(C₁-C₄)-alkyl]₂, (k) --CH₂ SO₂ NH-heteroaryl, (l) --SO₂ NH--CO--R¹⁴, (m)--CH₂ SO₂ NH--CO--R¹⁴, (n) --CONH--SO₂ R¹⁴, (o) --CH₂ CONH--SO₂ R¹⁴, (p)--NHSO₂ NHCO--R¹⁴, (q) --NHCONHSO₂ --R¹⁴, (r) --NHCO₂ R^(2a), ##STR56##R¹⁴ is (a) aryl, (b) heteroaryl, (c) (C₃ -C₇)-cycloalkyl, or (d) (C₁-C₄)-alkyl, unsubstituted or substituted with a substituent selectedfrom the group consisting of: aryl, heteroaryl, --OH, --SH, (C₁-C₄)-alkyl, --(C₁ -C₄)-alkoxy, --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I,--NO₂, --CO₂ H, CO₂ --(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃H or PO(OH)(O--(C₁ -C₄)-alkyl; R¹⁵ is(a) H, (b) aryl, which isunsubstituted or substituted with 1 or 2 substituents selected from thegroup consisting of: Cl, Br, I, F --O--(C₁ -C₄)-alkyl, (C₁ -C₄)-alkyl,--NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl, --OH, --NH₂, (C₃-C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl; (c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenylor (C₂ -C₆)-alkynyl each of which is unsubstituted or substituted withone or more substituents selected from the group consisting of: aryl,(C₃ -C₇)-cycloalkyl, Cl, Br, I, F, --OH, --NH₂, --NH[(C₁ -C₄)-alkyl],--N[(C₁ -C₄)-alkyl]₂, --NH--SO₂ R^(2a), --COOR^(2a), --SO₂ NHR^(2a) ; or(d) an unsubstituted, monosubstituted or disubstituted hetero arylselected from the group consisting of pyridyl, thienyl, furyl,imidazolyl and thiazolyl, and wherein the substituents are membersselected from the group consisting of --OH, --SH, (C₁ -C₄)-alkyl, (C₁-C₄)-alkyloxy, --CF₃, Cl, Br, I, F, or NO₂ ; and R¹⁹ is:(a) H, (b) (C₁-C₆)-alkyl, (c) (C₂ -C₄)-alkenyl, (d) (C₁ -C₄)-alkoxy, or (e) benzyl,wherein the phenyl is unsubstituted or substituted with a substituentselected from the group consisting of: --NO₂, --NH₂, --OH or --OCH₃ ;R²⁰ is --CN, --NO₂, --CO₂ R^(2a), or --CF₃ ; and R²¹ is:(a) aryl, or (b)(C₁ -C₄)-alkyl, is unsubstituted or substituted with:i) NH₂, ii) NH[(C₁-C₄)-alkyl], iii) N[(C₁ -C₄)-alkyl]₂, iv) CO₂ H, v) CO₂ (C₁ -C₄)-alkyl,vi) OH, vii) SO₃ H, or viii) SO₂ NH₂ ; or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1 wherein:R¹ is:(a) (C₁-C₆)-alkyl or (C₂ -C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which isunsubstituted or substituted with a substituent selected from the groupconsisting of:i) (C₁ -C₄)-alkylthio, ii) (C₁ -C₄)-alkoxy, iii) CF₃, iv)CF₂ CF₃, or v) (C₃ -C₅)-cycloalkyl, (b) perfluoro-(C₁ -C₄)-alkyl, or (c)(C₃ -C₅)-cycloalkyl; E is:(a) single bond, (b) --S--, or (c) --O--; J¹is (a)--C(═M)--, (b) J¹ and L are connected together to form a 6-carbonaromatic ring substituted with R^(7a), R^(7b), R^(8a) and R^(8b) or (c)J¹ and L are connected together to form a 6-membered aromatic ringcontaining one nitrogen atom not at J¹, substituted with R^(7a), R^(7b),R^(8a) and R^(8b) ; K¹ is (a)--C(═M)--, or (b) K¹ and L are connectedtogether to form a 6-carbon aromatic ring substituted with R^(7a),R^(7b), R^(8a) and R^(8b), or (c) K¹ and L are connected together toform a six-membered aromatic ring containing one nitrogen atomsubstituted with R^(7a), R^(7b) and R^(8a) provided that one and onlyone of J¹ and K¹ is --C(═M)--; one of a¹ or b¹ is a double bond instructure Ia provided that when J¹ is --C(═M)-- then b¹ is a double bondand when K¹ is --C(═M)-- then a¹ is a double bond; L is the point ofattachment of the 6-membered fused aromatic ring optionally containingone nitrogen atom; M is O, S or NR¹⁵ ; R² is:(a) H, (b) (C₁ -C₆)-alkyl;R^(2a) is:(a) R², (b) CH₂ aryl, or (c) aryl; R^(7a) and R^(7b) areindependently(a) H, (b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂-C₆)-alkynyl, (c) Cl, Br, I, F, (d) CF₃, or (e) when R^(7a) and R^(7b)are bonded to adjacent carbon atoms, they can be joined to form a phenylring; R^(8a) and R^(8b) are independently(a) H, (b) aryl-(C₁ -C₄)-alkyl,(c) heteroaryl-(C₁ -C₄)-alkyl, (d) (C₁ -C₆)-alkyl, is unsubstituted orsubstituted with a substituent selected from the group consisting of--CON(R^(2a))₂, --heteroaryl, --S(O)_(x) --R²¹, --tetrazol-5-yl,--CONHSO₂ R²¹, --SO₂ NH-heteroaryl, --SO₂ NHCOR²¹, --PO(OR²)₂,--PO(OR^(2a))₂, --SO₂ NH--CN, --NR² COOR²¹, --OH, --NH₂, guanidino, (C₁-C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), --O--COR^(2a), or aryl,(e) --CO-aryl, (f) (C₃ -C₇)-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i)--OR²¹, (j) --SH, (k) --S(O)_(n) --(C₁ -C₄)-alkyl, (l) --COR^(2a), (m)--CO₂ H, (n) --CO₂ --(C₁ -C₄)-alkyl, (o) --SO₃ H, (p) --NR² R²¹, (q)--NR² COR²¹, (r) --NR² COOR²¹, (s) --SO₂ NR^(2a), (t) --SO₂ NR² R^(2a),(u) --NO₂, (v) --NHSO₂ CF₃, (w) --CONR^(2a) R^(2a), (x) --(C₁-C₄)-perfluoroalkyl, (y) --COOR², (z) --SO₃ H, (aa) --N(R²)SO₂ R²¹, (bb)--NR² CONR^(2a) R²¹, (cc) --OC(═O)NR²¹ R^(2a), (dd) --aryl, (ee) --NHSO₂CF₃, (ff) --SO₂ NH-heteroaryl, (gg) --SO₂ NHCOR²¹, (hh) --CONHSO₂ R²¹,(ii) --PO(OR² ₂, (jj) --tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll)--SO₂ NHCN, or (mm) --heteroaryl; X is:(a) O, (b) H; H, (c) H; CO₂ --(C₁-C₄)-alkyl, (d) H; CO₂ H, (e) H; CN, (f) H; tetrazolyl, or (g) H;CONHSO₂ R¹⁴, R⁹ and R¹⁰ are each independently:(a) H, (b) Cl, Br, I, F,(c) NO₂, (d) (C₁ -C₆)-alkyl, (e) (C₁ -C₆)-acyloxy, (f) (C₃-C₆)-cycloalkyl, (g) (C₁ -C₆)-alkoxy, (h) --NHSO₂ R^(2a), (i)hydroxy-(C₁ -C₄)-alkyl, (j) (C₁ -C₄)-alkyl-aryl, (k) S(O)_(n) --(C₁-C₄)-alkyl, (n) NR^(2a) R^(2a), (q) CF₃, (r) --SO₂ NHR^(2a), (s) furyl,(t) aryl, wherein aryl is phenyl or naphthyl, unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of: Cl, Br, I, F, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, NO₂, CF₃,(C₁ -C₄)-alkylthio, OH, NH₂, --NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂,--CO₂ H, or --CO₂ --(C₁ -C₄)-alkyl, or (u) when R⁹ and R¹⁰ are bonded toadjacent carbon atoms, they can be joined to form an aryl ring; R¹¹ andR¹² are independently:(a) H, (b) Cl, Br, I, F, (c) NO₂, (d) NH₂, (e)NH[(C₁ -C₄)-alkyl], (f) N[(C₁ -C₄)-alkyl]₂, (g) SO₂ NHR^(2a), (h) CF₃,(i) (C₁ -C₄)-alkyl, (j) (C₁ -C₄)-alkoxy, or (k) when R¹¹ and R¹² arebonded to adjacent carbon atoms, they can be joined to form an arylring; Z is:(a) H, (b) --CO₂ R^(2a), (c) --NHSO₂ CF₃, (d) --SO₂ NHR^(2a),(e) --CN, (f) --SO₂ NH-heteroaryl, wherein heteroaryl is anunsubstituted, monosubstituted or disubstituted five or six memberedaromatic ring which can optionally contain from 1 to 3 heteroatomsselected from the group consisting of O, N or S and wherein thesubstituents are members selected from the group consisting of --OH,--SH, --(C₁ -C₄)-alkyl, --(C₁ -C₄)-alkoxy, --CF₃, Cl, Br, F, I, --NO₂,--CO₂ H, --CO₂ --C₁ -C₄ -alkyl, --NH₂ NH[(C₁ -C₄)-alkyl] and --N[(C₁ -C₄-alkyl]₂, (g) --1H-tetrazol-5-yl, (h) --CH₂ -1H-tetrazol-5-yl, (i)--CONH-1H-tetrazol-5-yl, or (j) --SO₂ NHCOR¹⁴ ; R¹⁵ is:(a) H, (b) aryl,is unsubstituted or substituted with 1 or 2 substituents selected fromthe group consisting of Cl, Br, I, F, --O--(C₁ -C₄)-alkyl, (C₁-C₄)-alkyl, --NO₂, --CF₃, --SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl, --OH,--NH₂, (C₃ -C₇)-cycloalkyl, (C₃ -C₁₀)-alkenyl; (c) (C₁ -C₆)-alkyl, (C₂-C₆)-alkenyl or (C₂ -C₆)-alkynyl each of which is unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of: aryl, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F, --OH, --NH₂,--NH[(C₁ -C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂ R^(2a),--COOR^(2a), --SO₂ NHR^(2a) ; or (d) an unsubstituted, monosubstitutedor disubstituted hetero aryl selected from the group consisting ofpyridyl, thienyl, furyl, imidazolyl and thiazolyl, and wherein thesubstituents are members selected from the group consisting of --OH,--SH, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ;and R²¹ is:(a) aryl, or (b) (C₁ -C₄)-alkyl which is unsubstituted orsubstituted with:i) NH₂, ii) NH[(C₁ -C₄)-alkyl], iii) N[(C₁-C₄)-alkyl]₂, iv) CO₂ H, v) CO₂ (C₁ -C₄)-alkyl, vi) OH, vii) SO₃ H, orviii) SO₂ NH₂ ; or a pharmaceutically acceptable salt thereof.
 3. Thecompound of claim 1 wherein:R¹ is:(a) (C₁ -C₆)-alkyl (C₂ -C₆)-alkenyl or(C₂ -C₆)-alkynyl each of which is unsubstituted or substituted with asubstituent selected from the group consisting of:i) (C₁ -C₄)-alkylthio,ii) (C₁ -C₄)-alkoxy, iii) CF₃, iv) CF₂ CF₃, or v) (C₃ -C₅)-cycloalkyl,or (b) (C₁ -C₄)-perfluoroalkyl; E is a single bond; J¹ and L areconnected together to form a 6-carbon aromatic ring substituted withR^(7a), R^(7b), R^(8a) and R^(8b) ; or J¹ and L are connected togetherto form a 6-membered aromatic ring containing one nitrogen atom not atJ¹, substituted with R^(7a), R^(7b), R^(8a) and R^(8b) ; K¹ is--C(═M)--; a¹ is a double bond; L is the point of attachment of the6-membered fused aromatic ring optionally containing one nitrogen atom;M is O, or NR¹⁵ ; R² is:(a) H, (b) (C₁ -C₆)-alkyl, or (c) (C₁-C₆)-alkyl; R^(2a) is:(a) R², (b) benzyl, or (c) phenyl; R^(7a) andR^(7b) are independently:(a) H, (b) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or(C₂ -C₆)-alkynyl, (c) Cl, Br, I, F, (d) CF₃, or (e) when R^(7a) andR^(7b) are bonded to adjacent carbon atoms, they can be joined to form aphenyl ring; R^(8a) and R^(8b) are independently:(a) H, (b) aryl-(C₁-C₄)-alkyl, (c) heteroaryl-(C₁ -C₄)-alkyl, (d) (C₁ -C₆)-alkyl,unsubstituted or substituted with a substituent selected from the groupconsisting of: --CON(R^(2a))₂, --heteroaryl, --S(O)_(n) --R²¹,--tetrazol-5-yl, --CONHSO₂ R²¹, --SO₂ NH-heteroaryl, --SO₂ NHCOR²¹,--PO(OR²)₂, --PO(OR^(2a))₂, --SO₂ NH--CN, --NR² COOR²¹, --OH, --NH₂,guanidino, (C₁ -C₄)-alkoxy, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylamino, (C₁-C₄)-dialkylamino, --COOR^(2a), --CONHR^(2a), --O--COR^(2a), or aryl,(e) --CO-aryl, (f) (C₃ -C₇)-cycloalkyl, (g) Cl, Br, I, F, (h) --OH, (i)--OR²¹, (j) --SH, (k) --S(O)_(n) --(C₁ -C₄)-alkyl, (l) --COR^(2a), (m)--CO₂ H, (n) --CO₂ --(C₁ -C₄)-alkyl, (o) --SO₃ H, (p) --NR² R²¹, (q)--NR² COR²¹, (r) --NR² COOR²¹, (s) --SO₂ NR^(2a), (t) --SO₂ NR² R^(2a),(u) --NO₂, (v) --NHSO₂ CF₃, (w) --CONR^(2a) R^(2a), (x) --(C₁-C₄)-perfluoroalkyl, (y) --COOR², (z) --SO₃ H, (aa) --N(R² SO₂ R²¹, (bb)--NR² CONR⁴ R²¹, (cc) --OC(═O)NR²¹ R^(2a), (dd) --aryl, (ee) --NHSO₂CF₃, (ff) --SO₂ NH-heteroaryl, (gg) --SO₂ NHCOR²¹, (hh) --CONHSO₂ R²¹,(ii) --PO(OR²)₂, (jj) --tetrazol-5-yl, (kk) --CONH(tetrazol-5-yl), (ll)--SO₂ NHCN, or (mm) --heteroaryl; X is:(a) O, (b) H; H, (c) H; CO₂ --(C₁-C₄)-alkyl, (d) H; CO₂ H, (e) H; CN, (f) H; tetrazolyl, or (g) H;CONHSO₂ R¹⁴, R¹¹ and R¹² are independently:(a) H, (b) Cl, Br, I, F, (c)NH₂, (d) NH[(C₁ -C₄)-alkyl], (e) N[(C₁ -C₄)-alkyl]₂ (f) SO₂ NHR^(2a),(g) CF₃, (h) C₁ -C₄ -alkyl, (i) C₁ -C₄ -alkoxy, or Z is:(a) H, (b) --CO₂R^(2a), (c) --NHSO₂ CF₃, (d) --SO₂ NHR¹⁴, (e) --1H-tetrazol-5-yl, (f)--SO₂ NHCOR¹⁴, or (g) --NHSO₂ R¹⁴ ; R¹⁴ is(a) aryl, (b) heteroaryl, (c)(C₃ -C₇)-cycloalkyl, or (d) (C₁ -C₄)-alkyl, unsubstituted or substitutedwith a substituent selected from the group consisting of aryl as definedabove, heteroaryl as defined above, --OH, --SH, (C₁ -C₄)-alkyl, --(C₁-C₄ -alkoxy), --S(C₁ -C₄)-alkyl, --CF₃, Cl, Br, F, I, --NO₂, --CO₂ H,CO₂ --(C₁ -C₄)-alkyl, --NH₂, --N[(C₁ -C₄)-alkyl]₂, --PO₃ H,PO(OH)(O--(C₁ -C₄)-alkyl; R¹⁵ is:(a) H, (b) aryl, unsubstituted orsubstituted with 1 or 2 substituents selected from the group consistingof: Cl, Br, I, F --O--(C₁ -C₄)-alkyl, (C₁ -C₄)-alkyl, --NO₂, --CF₃,--SO₂ NR² R^(2a), --S--(C₁ -C₄)-alkyl, --OH, --NH₂, (C₃ -C₇)-cycloalkyl,(C₃ -C₁₀)-alkenyl; (c) (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or (C₂-C₆)-alkynyl each of which is unsubstituted or substituted with one ormore substituents selected from the group consisting of aryl as definedabove, (C₃ -C₇)-cycloalkyl, Cl, Br, I, F, --OH, --NH₂, --NH[(C₁-C₄)-alkyl], --N[(C₁ -C₄)-alkyl]₂, --NH--SO₂ R^(2a), --COOR^(2a), --SO₂NHR^(2a) ; or (d) an unsubstituted, monosubstituted or disubstitutedheteroaryl selected from the group consisting of pyridyl, thienyl,furyl, imidazolyl and thiazolyl, and wherein the substituents aremembers selected from the group consisting of: --OH, --SH, (C₁-C₄)-alkyl, (C₁ -C₄)-alkyloxy --CF₃, Cl, Br, I, F, or NO₂ ; and R²¹is(a) aryl, or (b) (C₁ -C₄)-alkyl which is substituted or substitutedwith:i) NH₂, ii) NH[(C₁ -C₄)-alkyl], iii) N[(C₁ -C₄)-alkyl]₂, iv) CO₂ H,v) CO₂ (C₁ -C₄)-alkyl, vi) OH, vii) SO₃ H, or viii) SO₂ NH₂, iii) N[(C₁-C₄)-alkyl]₂, iv) CO₂ H, v) CO₂ (C₁ -C₄)-alkyl, vi) OH, vii) SO₃ H, orviii) SO₂ NH₂.
 4. The compound of claim 1 of structural formula##STR57## or a pharmaceutically acceptable salt thereof.
 5. The compoundof claim 1 of structural formula ##STR58## or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 1 of structuralformula ##STR59## or a pharmaceutically acceptable salt thereof.
 7. Acompound of structural formula ##STR60## wherein R¹ is: ethyl, n-propyl,n-butyl;R^(8b) is:N(n butyl)CO-phenyl, N(pentyl)CO-phenyl,N(benzyl))CO-phenyl, N(benzyl)CO₂ isobutyl, N(pentyl)CO-4-pyridyl,N(pentyl)CO-(4-chlorophenyl), N(n butyl)CO-(4-fluorophenyl),N(methyl)CO₂ -isobutyl, isopropyl, or N(benzyl)CON(methyl)(ethyl); Xis:(a) H; CO₂ (C₁ -C₄) alkyl, (b) H; CO₂ H, (c) H; CN, (d) H; 1Htetrazol-5-yl, or (e) H; CONHSO₂ R¹⁴ ; R¹⁰ is: H or (C₁ -C₃)-alkyl; andR¹¹ and R¹² are independently:H, CH₃, Cl, Br, OCH₃, or CF₃.
 8. Acompound of structural formula ##STR61## wherein R¹ is: ethyl, n-propyl,n-butyl;R^(8b) is:N(N-butyl)CO-phenyl, N(pentyl)CO-phenyl,N(benzyl))CO-phenyl, N(benzyl)CO₂ isobutyl, N(pentyl)CO-4-pyridyl,N(pentyl)CO-(4-chlorophenyl), N(n-butyl)CO-(4 fluorophenyl),N(methyl)CO₂ -isobutyl, isopropyl, or N(benzyl)CON(methyl)(ethyl); Xis:(a) O, or (b) H; H; R¹⁰ is: H or (C₁ -C₃)-alkyl, R¹¹ is:H, CH₃, Cl,Br, OCH₃, or CF₃ ; and Z is: --CO₂ R^(2a), --SO₂ NHR¹⁴, or--1H-tetrazol-5-yl.
 9. A pharmaceutical composition useful in thetreatment of hypertension which comprises a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.10. A method of treating hypertension which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim
 1. 11. A method of treating ocular hypertensioncomprising topical ocular administration to a patient in need of suchtreatment of an effective ocular antihypertensive amount of a compoundof claim
 1. 12. A method of treating cognitive dysfunction, anxiety, ordepression comprising administering to a patient in need of suchtreatment, a therapeutically effective amount of a compound of claim 1.